Fused tricyclic heterocyclic compounds as HIV integrase inhibitors

ABSTRACT

The present invention relates to Fused Tricyclic Heterocycle Derivatives of Formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 -R 8 , A, X and n are as defined herein. The present invention also relates to compositions comprising at least one Fused Tricyclic Heterocycle Derivative, and methods of using the Fused Tricyclic Heterocycle Derivatives for treating or preventing HIV infection in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national stage application under 35 U.S.C. 371of International Patent Application No. PCT/CN2014/075685, filed Apr.18, 2014, which claims priority to U.S. Provisional Application No.61/824,739, filed May 17, 2013. Each of the aforementioned PCT andpriority applications is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to Fused Tricyclic HeterocycleDerivatives, compositions comprising at least one Fused TricyclicHeterocycle Derivative, and methods of using the Fused TricyclicHeterocycle Derivatives for treating or preventing HIV infection in asubject.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV), particularlythe strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus,is the etiological agent of the complex disease that includesprogressive destruction of the immune system (acquired immune deficiencysyndrome; AIDS) and degeneration of the central and peripheral nervoussystem. A common feature of retrovirus replication is the insertion byvirally-encoded integrase of +proviral DNA into the host cell genome, arequired step in HIV replication in human T-lymphoid and monocytoidcells. Integration is believed to be mediated by integrase in threesteps: assembly of a stable nucleoprotein complex with viral DNAsequences; cleavage of two nucleotides from the 3′ termini of the linearproviral DNA; covalent joining of the recessed 3′ OH termini of theproviral DNA at a staggered cut made at the host target site. The fourthstep in the process, repair synthesis of the resultant gap, may beaccomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Aminoacid sequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh, H. et al.,EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986);Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes havebeen shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhibitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication.

The following references are of interest as background:

International Publication Nos. WO 11/045330 and WO 11/121105 disclosemacrocyclic compounds having HIV integrase inhibitory activity.

Kinzel et al., Tet. Letters 2007, 48(37): pp. 6552-6555 discloses thesynthesis of tetrahydropyridopyrimidones as a scaffold for HIV-1integrase inhibitors.

Ferrara et al., Tet. Letters 2007, 48(37), pp. 8379-8382 discloses thesynthesis of a hexahydropyrimido[1,2-a]azepine-2-carboxamide derivativeuseful as an HIV integrase inhibitor.

Muraglia et al., J. Med. Chem. 2008, 51: 861-874 discloses the designand synthesis of bicyclic pyrimidinones as potent and orallybioavailable HIV-1 integrase inhibitors.

US2004/229909 discloses certain compounds having integrase inhibitoryactivity.

U.S. Pat. No. 7,232,819 and US 2007/0083045 disclose certain5,6-dihydroxypyrimidine-4-carboxamides as HIV integrase inhibitors.

U.S. Pat. No. 7,169,780, U.S. Pat. No. 7,217,713, and US 2007/0123524disclose certain N-substituted5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides as HIV integraseinhibitors.

U.S. Pat. No. 7,279,487 discloses certain hydroxynaphthyridinonecarboxamides that are useful as HIV integrase inhibitors.

U.S. Pat. No. 7,135,467 and U.S. Pat. No. 7,037,908 disclose certainpyrimidine carboxamides that are useful as HIV integrase inhibitors.

U.S. Pat. No. 7,211,572 discloses certain nitrogenous condensed ringcompounds that are HIV integrase inhibitors.

U.S. Pat. No. 7,414,045 discloses certaintetrahydro-4H-pyrido[1,2-a]pyrimidine carboxamides,hexahydropyrimido[1,2-a]azepine carboxamides, and related compounds thatare useful as HIV integrase inhibitors.

WO 2006/103399 discloses certain tetrahydro-4H-pyrimidooxazepinecarboxamides, tetrahydropyrazinopyrimidine carboxamides,hexahydropyrimidodiazepine carboxamides, and related compounds that areuseful as HIV integrase inhibitors.

US 2007/0142635 discloses processes for preparinghexahydropyrimido[1,2-a]azepine-2-carboxylates and related compounds.

US 2007/0149556 discloses certain hydroxypyrimidinone derivatives havingHIV integrase inhibitory activity.

Various pyrimidinone compounds useful as HIV integrase inhibitors arealso disclosed in U.S. Pat. No. 7,115,601, U.S. Pat. No. 7,157,447, U.S.Pat. No. 7,173,022, U.S. Pat. No. 7,176,196, U.S. Pat. No. 7,192,948,U.S. Pat. No. 7,273,859, and U.S. Pat. No. 7,419,969.

US 2007/0111984 discloses a series of bicyclic pyrimidinone compoundsuseful as HIV integrase inhibitors.

US 2006/0276466, US 2007/0049606, US 2007/0111985, US 2007/0112190, US2007/0281917, US 2008/0004265 each disclose a series of bicyclicpyrimidinone compounds useful as HIV integrase inhibitors.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides Compounds of Formula (I):

and pharmaceutically acceptable salts and prodrugs thereof,wherein:

A is C₁-C₄ alkylene, C₂-C₄ alkenylene, arylene, C₃-C₇ cycloalkyl, 5 or6-membered monocyclic heteroaryl, 4 to 7-membered heterocycloalkyl, —O—,—NH—C(O)—, —C(O)NH— or —C(O)—;

X is O, —N(C₁-C₆ alkyl)- or —C(R¹⁰)(R¹¹), such that when X═O or —N(C₁-C₆alkyl)-, then R⁴, R⁵, R⁶ and R⁷ are each other than —OR⁹, —N(R⁹)₂ orhalo;

each occurrence of m is independently 0 or 1;

n is 0 or 1, such that when n is 0, then R⁴ and R⁵ are not present;

R¹ is C₁-C₆ alkyl, which is optionally substituted with up to 3 groups,each independently selected from C₃-C₇ cycloalkyl, 5 or 6-memberedmonocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl,C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂,—NHC(O)R⁹ and —SR⁹, wherein said C₃-C₇ cycloalkyl group, said 5 or6-membered monocyclic heteroaryl group, said 4 to 6-membered monocyclicheterocycloalkyl group and said C₆-C₁₀ aryl group can each be optionallyand independently substituted with one or more groups, eachindependently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5 or6-membered monocyclic heteroaryl, 4 to 6-membered monocyclicheterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂,—C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹;

R², R⁵, R⁶, R⁷, R¹⁰ and R¹¹ are each independently selected from H,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂,—C(O)R⁹, —C(O)N(R⁹)₂ and —NHC(O)R⁹, wherein said C₁-C₆ alkyl group canbe optionally substituted with one or more groups, each independentlyselected from halo, —OH, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —SH or —S(C₁-C₆ alkyl);

R³ is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, —C(O)R⁹,—C(O)N(R⁹)₂ and —NHC(O)R⁹, wherein said C₁-C₆ alkyl group can beoptionally substituted with one or more groups, each independentlyselected from halo, —OH, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —SH or —S(C₁-C₆ alkyl);

R⁴ is H, or R⁴ and R⁵ and the common carbon atom to which they areattached, join to form an endocyclic —C(O)— group;

R⁸ is selected from C₁-C₆ alkyl, —(C₁-C₃ alkylene)_(m)-(C₃-C₇cycloalkyl), —(C₁-C₃ alkylene)_(m)-(5 or 6-membered monocyclicheteroaryl), —(C₁-C₃ alkylene)_(m)-(4 to 6-membered monocyclicheterocycloalkyl) and —(C₁-C₃ alkylene)_(m)-(C₆-C₁₀ aryl), wherein saidC₃-C₇ cycloalkyl group, said 5 or 6-membered monocyclic heteroarylgroup, said 4 to 6-membered monocyclic heterocycloalkyl group and saidC₆-C₁₀ aryl group can each be optionally and independently substitutedwith up to 5 groups, each independently selected from C₁-C₆ alkyl, C₃-C₇cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-memberedmonocyclic heterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹,—N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; and

each occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.

The Compounds of Formula (I) (also referred to herein as the “FusedTricyclic Heterocycle Derivatives”) and pharmaceutically acceptablesalts thereof can be useful, for example, for inhibiting HIV viralreplication or replicon activity, and for treating or preventing HIVinfection in a subject. Without being bound by any specific theory, itis believed that the Fused Tricyclic Heterocycle Derivatives inhibit HIVviral replication by inhibiting HIV Integrase.

Accordingly, the present invention provides methods for treating orpreventing HIV infection in a subject, comprising administering to thesubject an effective amount of at least one Fused Tricyclic HeterocycleDerivative.

The details of the invention are set forth in the accompanying detaileddescription below.

Although any methods and materials similar to those described herein canbe used in the practice or testing of the present invention,illustrative methods and materials are now described. Other embodiments,aspects and features of the present invention are either furtherdescribed in or will be apparent from the ensuing description, examplesand appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to Fused Tricyclic HeterocycleDerivatives, compositions comprising at least one Fused TricyclicHeterocycle Derivative, and methods of using the Fused TricyclicHeterocycle Derivatives for inhibiting HIV integrase, inhibiting HIVviral replication or for treating or preventing HIV infection in asubject.

DEFINITIONS AND ABBREVIATIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“—O-alkyl,” etc. . . . .

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “subject” is a human or non-human mammal. In one embodiment, a subjectis a human. In another embodiment, a subject is a primate. In anotherembodiment, a subject is a monkey. In another embodiment, a subject is achimpanzee. In still another embodiment, a subject is a rhesus monkey.

The term “effective amount” as used herein, refers to an amount of FusedTricyclic Heterocycle Derivative and/or an additional therapeutic agent,or a composition thereof that is effective in producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect whenadministered to a subject suffering from HIV infection or AIDS. In thecombination therapies of the present invention, an effective amount canrefer to each individual agent or to the combination as a whole, whereinthe amounts of all agents administered are together effective, butwherein the component agent of the combination may not be presentindividually in an effective amount.

The term “preventing,” as used herein with respect to an HIV viralinfection or AIDS, refers to reducing the likelihood or severity of HIVinfection or AIDS.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup having one of its hydrogen atoms replaced with a bond. An alkylgroup may be straight or branched and contain from about 1 to about 20carbon atoms. In one embodiment, an alkyl group contains from about 1 toabout 12 carbon atoms. In different embodiments, an alkyl group containsfrom 1 to 6 carbon atoms (C₁-C₆ alkyl) or from about 1 to about 4 carbonatoms (C₁-C₄ alkyl). Non-limiting examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl andneohexyl. An alkyl group may be unsubstituted or substituted by one ormore substituents which may be the same or different, each substituentbeing independently selected from the group consisting of halo, alkenyl,alkynyl, aryl, cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl,-alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂,—NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl,—C(O)OH and —C(O)O-alkyl. In one embodiment, an alkyl group is linear.In another embodiment, an alkyl group is branched. Unless otherwiseindicated, an alkyl group is unsubstituted.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and having oneof its hydrogen atoms replaced with a bond. An alkenyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkenyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groupsinclude ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl,octenyl and decenyl. An alkenyl group may be unsubstituted orsubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy,—O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. The term “C₂-C₆ alkenyl”refers to an alkenyl group having from 2 to 6 carbon atoms. Unlessotherwise indicated, an alkenyl group is unsubstituted.

The term “alkynyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and having oneof its hydrogen atoms replaced with a bond. An alkynyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkynyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkynyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynylgroup may be unsubstituted or substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkenyl, alkynyl, aryl,cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl,alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. The term“C₂-C₆ alkynyl” refers to an alkynyl group having from 2 to 6 carbonatoms. Unless otherwise indicated, an alkynyl group is unsubstituted.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 toabout 6 carbon atoms. In another embodiment, an alkylene group has fromabout 3 to about 5 carbon atoms. In another embodiment, an alkylenegroup is branched. In another embodiment, an alkylene group is linear.In one embodiment, an alkylene group is —CH₂—. The term “C₁-C₆ alkylene”refers to an alkylene group having from 1 to 6 carbon atoms. The term“C₃-C₅ alkylene” refers to an alkylene group having from 3 to 5 carbonatoms.

The term “alkenylene,” as used herein, refers to an alkenyl group, asdefined above, wherein one of the alkenyl group's hydrogen atoms hasbeen replaced with a bond. Non-limiting examples of alkenylene groupsinclude —CH═CH—, —CH═CHCH₂—, —CH₂CH═CH—, —CH₂CH═CHCH₂—, —CH═CHCH₂CH₂—,—CH₂CH₂CH═CH— and —CH(CH₃)CH═CH—. In one embodiment, an alkenylene grouphas from 2 to about 6 carbon atoms. In another embodiment, an alkenylenegroup has from about 2 to about 4 carbon atoms. In another embodiment,an alkenylene group is branched. In another embodiment, an alkenylenegroup is linear. The term “C₂-C₆ alkylene” refers to an alkenylene grouphaving from 2 to 6 carbon atoms. The term “C₂-C₄ alkenylene” refers toan alkylene group having from 2 to 4 carbon atoms.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to about10 carbon atoms. An aryl group can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein below. In one embodiment, an aryl group can beoptionally fused to a cycloalkyl or cycloalkanoyl group. Non-limitingexamples of aryl groups include phenyl and naphthyl. In one embodiment,an aryl group is phenyl. Unless otherwise indicated, an aryl group isunsubstituted.

The term “arylene,” as used herein, refers to a bivalent group derivedfrom an aryl group, as defined above, by removal of a hydrogen atom froma ring carbon of an aryl group. An arylene group can be derived from amonocyclic or multicyclic ring system comprising from about 6 to about14 carbon atoms. In one embodiment, an arylene group contains from about6 to about 10 carbon atoms. In another embodiment, an arylene group is anaphthylene group. In another embodiment, an arylene group is aphenylene group. An arylene group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein below. An arylene group is divalent and eitheravailable bond on an arylene group can connect to either group flankingthe arylene group. For example, the group “A-arylene-B,” wherein thearylene group is:

is understood to represent both:

In one embodiment, an arylene group can be optionally fused to acycloalkyl or cycloalkanoyl group. Non-limiting examples of arylenegroups include phenylene and naphthalene. In one embodiment, an arylenegroup is unsubstituted. In another embodiment, an arylene group is:

Unless otherwise indicated, an arylene group is unsubstituted.

The term “cycloalkyl,” as used herein, refers to a non-aromatic mono- ormulticyclic ring system comprising from about 3 to about 10 ring carbonatoms. In one embodiment, a cycloalkyl contains from about 5 to about 10ring carbon atoms. In another embodiment, a cycloalkyl contains fromabout 3 to about 7 ring atoms. In another embodiment, a cycloalkylcontains from about 5 to about 6 ring atoms. The term “cycloalkyl” alsoencompasses a cycloalkyl group, as defined above, which is fused to anaryl (e.g., benzene) or heteroaryl ring. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples ofmulticyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. Acycloalkyl group can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein below. In one embodiment, a cycloalkyl group isunsubstituted. The term “3 to 7-membered cycloalkyl” refers to acycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwiseindicated, a cycloalkyl group is unsubstituted. A ring carbon atom of acycloalkyl group may be functionalized as a carbonyl group. Anillustrative example of such a cycloalkyl group (also referred to hereinas a “cycloalkanoyl” group) includes, but is not limited to,cyclobutanoyl:

The term “halo,” as used herein, means —F, —Cl, —Br or —I.

The term “haloalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a halogen. In one embodiment, a haloalkyl grouphas from 1 to 6 carbon atoms. In another embodiment, a haloalkyl groupis substituted with from 1 to 3 F atoms. Non-limiting examples ofhaloalkyl groups include —CH₂F, —CHF₂, —CF₃, —CH₂Cl and —CCl₃. The term“C₁-C₆ haloalkyl” refers to a haloalkyl group having from 1 to 6 carbonatoms.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshave been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃. The term “C₁-C₆ hydroxyalkyl” refers to a hydroxyalkylgroup having from 1 to 6 carbon atoms.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 4 of the ring atoms is independently O, N or S and theremaining ring atoms are carbon atoms. In one embodiment, a heteroarylgroup has 5 to 10 ring atoms. In another embodiment, a heteroaryl groupis monocyclic and has 5 or 6 ring atoms. In another embodiment, aheteroaryl group is bicyclic. A heteroaryl group can be optionallysubstituted by one or more “ring system substituents” which may be thesame or different, and are as defined herein below. A heteroaryl groupis joined via a ring carbon atom, and any nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. The term“heteroaryl” also encompasses a heteroaryl group, as defined above,which is fused to a benzene ring. Non-limiting examples of heteroarylsinclude pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone(including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl,thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and allisomeric forms thereof. The term “heteroaryl” also refers to partiallysaturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In oneembodiment, a heteroaryl group is a 5-membered heteroaryl. In anotherembodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl. Inanother embodiment, a heteroaryl group comprises a 5- to 6-memberedmonocyclic heteroaryl group fused to a benzene ring. Unless otherwiseindicated, a heteroaryl group is unsubstituted.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to about 11ring atoms, wherein from 1 to 4 of the ring atoms are independently O,S, N or Si, and the remainder of the ring atoms are carbon atoms. Aheterocycloalkyl group can be joined via a ring carbon, ring siliconatom or ring nitrogen atom. In one embodiment, a heterocycloalkyl groupis monocyclic and has from about 3 to about 7 ring atoms. In anotherembodiment, a heterocycloalkyl group is monocyclic has from about 4 toabout 7 ring atoms. In another embodiment, a heterocycloalkyl group isbicyclic and has from about 7 to about 11 ring atoms. In still anotherembodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ringatoms. In one embodiment, a heterocycloalkyl group is monocyclic. Inanother embodiment, a heterocycloalkyl group is bicyclic. There are noadjacent oxygen and/or sulfur atoms present in the ring system. Any —NHgroup in a heterocycloalkyl ring may exist protected such as, forexample, as an —N(BOC), —N(Cbz), —N(Tos) group and the like; suchprotected heterocycloalkyl groups are considered part of this invention.The term “heterocycloalkyl” also encompasses a heterocycloalkyl group,as defined above, which is fused to an aryl (e.g., benzene) orheteroaryl ring. A heterocycloalkyl group can be optionally substitutedby one or more “ring system substituents” which may be the same ordifferent, and are as defined herein below. The nitrogen or sulfur atomof the heterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclicheterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone andthe like, and all isomers thereof.

A ring carbon atom of a heterocycloalkyl group may be functionalized asa carbonyl group. An illustrative example of such a heterocycloalkylgroup is:

In one embodiment, a heterocycloalkyl group is a 5-membered monocyclicheterocycloalkyl. In another embodiment, a heterocycloalkyl group is a6-membered monocyclic heterocycloalkyl. The term “3 to 6-memberedmonocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkylgroup having from 3 to 6 ring atoms. The term “4 to 7-memberedmonocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkylgroup having from 4 to 7 ring atoms. The term “7 to 11-membered bicyclicheterocycloalkyl” refers to a bicyclic heterocycloalkyl group havingfrom 7 to 11 ring atoms. Unless otherwise indicated, a heterocycloalkylgroup is unsubstituted.

The term “ring system substituent,” as used herein, refers to asubstituent group attached to an aromatic or non-aromatic ring systemwhich, for example, replaces an available hydrogen on the ring system.Ring system substituents may be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl,-alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl,—OH, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl, -alkylene-O-alkyl,—O-aryl, —O-alkylene-aryl, acyl, —C(O)-aryl, halo, —NO₂, —CN, —SF₅,—C(O)OH, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-alkylene-aryl, —S(O)-alkyl,—S(O)₂-alkyl, —S(O)-aryl, —S(O)₂-aryl, —S(O)-heteroaryl,—S(O)₂-heteroaryl, —S-alkyl, —S-aryl, —S-heteroaryl, —S-alkylene-aryl,—S-alkylene-heteroaryl, —S(O)₂-alkylene-aryl,—S(O)₂-alkylene-heteroaryl, —Si(alkyl)₂, —Si(aryl)₂, —Si(heteroaryl)₂,—Si(alkyl)(aryl), —Si(alkyl)(cycloalkyl), —Si(alkyl)(heteroaryl),cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),—N(Y₁)(Y₂), -alkylene-N(Y₁)(Y₂), —C(O)N(Y₁)(Y₂) and —S(O)₂N(Y₁)(Y₂),wherein Y₁ and Y₂ can be the same or different and are independentlyselected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl,and -alkylene-aryl. “Ring system substituent” may also mean a singlemoiety which simultaneously replaces two available hydrogens on twoadjacent carbon atoms (one H on each carbon) on a ring system. Examplesof such moiety are methylenedioxy, ethylenedioxy, —C(CH₃)₂— and the likewhich form moieties such as, for example:

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “in substantially purified form,” as used herein, refers to thephysical state of a compound after the compound is isolated from asynthetic process (e.g., from a reaction mixture), a natural source, ora combination thereof. The term “in substantially purified form,” alsorefers to the physical state of a compound after the compound isobtained from a purification process or processes described herein orwell-known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any substituent or variable (e.g., alkyl, R¹, R⁷, etc.) occurs morethan one time in any constituent or in Formula (I), its definition oneach occurrence is independent of its definition at every otheroccurrence, unless otherwise indicated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g., a drugprecursor) that is transformed in vivo to provide a Fused TricyclicHeterocycle Derivative or a pharmaceutically acceptable salt of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. For example, if a Fused Tricyclic HeterocycleDerivative or a pharmaceutically acceptable salt, hydrate or solvate ofthe compound contains a carboxylic acid functional group, a prodrug cancomprise an ester formed by the replacement of the hydrogen atom of theacid group with a group such as, for example, (C₁-C₈)alkyl,(C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbonatoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Fused Tricyclic Heterocycle Derivative contains analcohol functional group, a prodrug can be formed by the replacement ofone or more of the hydrogen atoms of the alcohol groups with a groupsuch as, for example, (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkyl,α-amino(C₁-C₄)alkylene-aryl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, or glycosyl (theradical resulting from the removal of a hydroxyl group of the hemiacetalform of a carbohydrate).

If a Fused Tricyclic Heterocycle Derivative incorporates an aminefunctional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as, for example,R-carbonyl-, RO-carbonyl-, NRR′-carbonyl- wherein R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, a naturalα-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl,—C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl; carboxy(C₁-C₆)alkyl; amino(C₁-C₄)alkyl or mono-N- ordi-N,N—(C₁-C₆)alkylaminoalkyl; —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N- or di-N,N—(C₁-C₆)alkylamino morpholino; piperidin-1-yl orpyrrolidin-1-yl, and the like.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy group of a hydroxyl compound, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g.,methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example,phenoxymethyl), aryl (e.g., phenyl optionally substituted with, forexample, halogen, C₁₋₄alkyl, —O—(C₁₋₄alkyl) or amino); (2) sulfonateesters, such as alkyl- or aralkylsulfonyl (for example,methanesulfonyl); (3) amino acid esters, including those correspondingto both natural and non-natural amino acids (e.g., L-valyl orL-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphateesters. The phosphate esters may be further esterified by, for example,a C₁₋₂₀ alcohol or reactive derivative thereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of solvates includeethanolates, methanolates, and the like. A “hydrate” is a solvatewherein the solvent molecule is water.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS Pharm Sci Techours., 5(1), article 12 (2004); and A. L. Binghamet al, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanroom temperature, and cooling the solution at a rate sufficient to formcrystals which are then isolated by standard methods. Analyticaltechniques such as, for example IR spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The Fused Tricyclic Heterocycle Derivatives can form salts which arealso within the scope of this invention. Reference to a Fused TricyclicHeterocycle Derivative herein is understood to include reference tosalts thereof, unless otherwise indicated. The term “salt(s)”, asemployed herein, denotes acidic salts formed with inorganic and/ororganic acids, as well as basic salts formed with inorganic and/ororganic bases. In addition, when a Fused Tricyclic HeterocycleDerivative contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. In one embodiment,the salt is a pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salt. In another embodiment, the salt isother than a pharmaceutically acceptable salt. Salts of the Compounds ofFormula (I) may be formed, for example, by reacting a Fused TricyclicHeterocycle Derivative with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, t-butyl amine, choline, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well-known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Sterochemically pure compounds may also be prepared by using chiralstarting materials or by employing salt resolution techniques. Also,some of the Fused Tricyclic Heterocycle Derivatives may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be directly separated using chiralchromatographic techniques.

It is also possible that the Fused Tricyclic Heterocycle Derivatives mayexist in different tautomeric forms, and all such forms are embracedwithin the scope of the invention. For example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, hydrates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention. If a Fused TricyclicHeterocycle Derivative incorporates a double bond or a fused ring, boththe cis- and trans-forms, as well as mixtures, are embraced within thescope of the invention.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Recitation or depiction of a specific compound in the claims (i.e., aspecies) without a specific stereoconfiguration designation, or withsuch a designation for less than all chiral centers, is intended toencompass the racemate, racemic mixtures, each individual enantiomer, adiastereoisomeric mixture and each individual diastereomer of thecompound where such forms are possible due to the presence of one ormore asymmetric centers.

In the Compounds of Formula (I), the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of generic Formula I.For example, different isotopic forms of hydrogen (H) include protium(¹H) and deuterium (²H). Protium is the predominant hydrogen isotopefound in nature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched Compoundsof Formula (I) can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates. In one embodiment, a Compound of Formula (I) has one ormore of its hydrogen atoms replaced with deuterium.

Polymorphic forms of the Fused Tricyclic Heterocycle Derivatives, and ofthe salts, solvates, hydrates, esters and prodrugs of the FusedTricyclic Heterocycle Derivatives, are intended to be included in thepresent invention.

General List of Abbreviations

-   AcOH=acetic acid-   Alk=alkyl-   Ar=aryl-   Boc=tert-butoxycarbonyl-   br=broad-   d=doublet-   DCE=1,2-dichloroethane-   DEA=N,N-diethylamine-   DHP=dihydropyran-   DIEA=N,N-diisopropylethylamine-   DMA=N,N-dimethylacetamide-   DMF=dimethylformamide-   DMSO=dimethyl sulfoxide-   EDC=1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride-   ESI=electrospray ionization-   EtOAc=ethyl acetate-   EtOH=ethanol-   HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate-   HOAt=1-hydroxy-7-azabenzotriazole-   HOBt=1-hydroxybenzotriazole-   HRMS=high resolution mass spectrometry-   LCMS=liquid chromatography/mass sepectrometry-   LiHMDS=lithium bis(trimethylsilyl)amide-   LRMS=low resolution mass spectrometry-   m=multiplet-   mCPBA=meta-chloroperoxybenzoic acid-   min=minutes-   MS=mass spectroscopy-   NMR=nuclear magnetic resonance spectroscopy-   Piv=pivalate, 2,2-dimethylpropanoyl-   Ph=phenyl-   s=singlet-   SFC=supercritical fluid chromatography-   t=triplet-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   wt %=weight percent

The Compounds of Formula (I)

The present invention provides Fused Tricyclic Heterocycle Derivativesof Formula (I):

and pharmaceutically acceptable salts thereof, wherein R¹-R⁸, n, A and Xare defined above for the Compounds of Formula (I).

In one embodiment, the Compounds of Formula (I) have Formula (Ia′):

and pharmaceutically acceptable salts thereof,wherein:

A is C₁-C₁ alkylene, C₂-C₄ alkenylene, arylene, C₃-C₇ cycloalkyl, 5 or6-membered monocyclic heteroaryl, 4 to 7-membered heterocycloalkyl, —O—,—NH—C(O)—, —C(O)NH— or —C(O)—;

X is O, —N(C₁-C₆ alkyl)- or —CH₂, such that when X═O or —N(C₁-C₆alkyl)-, then R⁴, R⁵, R⁶ and R⁷ are each other than —OR⁹, —N(R⁹)₂ orhalo;

n is 0 or 1;

R¹ is C₁-C₆ alkyl, which is optionally substituted with up to 3 groups,each independently selected from C₃-C₇ cycloalkyl, 5 or 6-memberedmonocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl,C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR¹¹, —N(R¹¹)₂, —C(O)R¹¹,—C(O)N(R¹¹)₂, —NHC(O)R¹¹ and —SR¹¹, wherein said C₃-C₇ cycloalkyl group,said 5 or 6-membered monocyclic heteroaryl group, said 4 to 6-memberedmonocyclic heterocycloalkyl group and said C₆-C₁₀ aryl group can each beoptionally and independently substituted with one or more groups, eachindependently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5 or6-membered monocyclic heteroaryl, 4 to 6-membered monocyclicheterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂,—C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹;

R², R⁵, R⁶ and R⁷ are each independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂, —C(O)R⁹,—C(O)N(R⁹)₂ and —NHC(O)R⁹, wherein said C₁-C₆ alkyl group can beoptionally substituted with one or more groups, each independentlyselected from halo, —OH, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —SH or —S(C₁-C₆ alkyl);

R³ is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, —C(O)R⁹,—C(O)N(R⁹)₂ and —NHC(O)R⁹, wherein said C₁-C₆ alkyl group can beoptionally substituted with one or more groups, each independentlyselected from halo, —OH, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —SH or —S(C₁-C₆ alkyl);

R⁴ is H, or R⁴ and R⁵ and the common carbon atom to which they areattached, join to form an endocyclic —C(O)— group;

R⁸ is selected from C₁-C₆ alkyl, —(C₁-C₃ alkylene)_(n)-(C₃-C₇cycloalkyl), —(C₁-C₃ alkylene)_(n)-(5 or 6-membered monocyclicheteroaryl), —(C₁-C₃ alkylene)_(n)-(4 to 6-membered monocyclicheterocycloalkyl) and —(C₁-C₃ alkylene)_(n)-(C₆-C₁₀ aryl), wherein saidC₃-C₇ cycloalkyl group, said 5 or 6-membered monocyclic heteroarylgroup, said 4 to 6-membered monocyclic heterocycloalkyl group and saidC₆-C₁₀ aryl group can each be optionally and independently substitutedwith up to 5 groups, each independently selected from C₁-C₆ alkyl, C₃-C₇cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-memberedmonocyclic heterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹,—N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; and

each occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.

In one embodiment, the Compounds of Formula (I) have Formula (Ia):

and pharmaceutically acceptable salts thereof,wherein:

A is 5 or 6-membered monocyclic heteroaryl or —NH—C(O)—;

X is O, —N(C₁-C₆ alkyl)- or —C(R¹⁰)(R¹¹), such that when X═O or —N(C₁-C₆alkyl)-, then R⁴, R⁵, R⁶ and R⁷ are each other than —OR⁹, —N(R⁹)₂ orhalo;

n is 0 or 1, such that when n is 0, then R⁴ and R⁵ are not present;

R¹ is C₁-C₆ alkyl, which is optionally substituted with a group selectedfrom phenyl, C₃-C₇ cycloalkyl, 5 or 6-membered monocyclic heteroaryl and—OR⁹, wherein said phenyl group and said 5 or 6-membered monocyclicheteroaryl group can each be optionally and independently substitutedwith up to two groups, each independently selected from C₁-C₆ alkyl,C₃-C₇ cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-memberedmonocyclic heterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹,—N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹;

R⁴ is H, or R⁴ and R⁵ and the common carbon atom to which they areattached, join to form an endocyclic —C(O)— group;

R⁵, R¹⁰ and R¹¹ are each independently selected from H, C₁-C₆ alkyl and—OR⁹;

R⁷ is selected from H, C₁-C₆ alkyl, —OR⁹ and —OH;

R⁸ is selected from C₁-C₆ alkyl or benzyl, wherein the phenyl moiety ofsaid benzyl group can be optionally and independently substituted withup to 3 groups, each independently selected from C₁-C₆ alkyl, C₃-C₇cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-memberedmonocyclic heterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹,—N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; and

each occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.

In one embodiment, the Compounds of Formula (I) have Formula (Ib):

and pharmaceutically acceptable salts and prodrugs thereof,wherein:

A is pyrazolyl, thiadiazolyl, triazolyl, thiazolyl, oxazolyl,oxadiazolyl or —NHC(O)—;

X is O, —N(C₁-C₆ alkyl)- or —C(R¹⁰)(R¹¹), such that when X═O or —N(C₁-C₆alkyl)-, then R⁴, R⁵, R⁶ and R⁷ are each other than —OR⁹, —N(R⁹)₂ orhalo;

n is 0 or 1, such that when n is 0, then R⁴ and R⁵ are not present;

R¹ is C₁-C₆ alkyl, which is optionally substituted with a group selectedfrom phenyl, C₃-C₇ cycloalkyl, 5 or 6-membered monocyclic heteroaryl and—O—(C₁-C₆ alkyl), wherein said phenyl group and said 5 or 6-memberedmonocyclic heteroaryl group can each be optionally and independentlysubstituted with up to two groups, each independently selected fromC₁-C₆ alkyl, halo and —O—(C₁-C₆ alkyl);

R⁴ is H, or R⁴ and R⁵ and the common carbon atom to which they areattached, join to form an endocyclic —C(O)— group;

R⁵, R¹⁰ and R¹¹ are each independently selected from H, C₁-C₆ alkyl and—O—(C₁-C₆ alkyl);

R⁷ is selected from H, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) and —OH;

R⁸ is selected from C₁-C₆ alkyl or benzyl, wherein the phenyl moiety ofsaid benzyl group can be optionally and independently substituted withup to 3 groups, each independently selected from C₁-C₆ alkyl, —O—(C₁-C₆alkyl) and halo; and

each occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.

In one embodiment, A is —NH—C(O)—.

In another embodiment, A is 5-membered heteroaryl.

In another embodiment, A is pyrazolyl, thiadiazolyl, triazolyl,thiazolyl, oxazolyl, oxadiazolyl or —NHC(O)—.

In still another embodiment, A is pyrazolyl, thiadiazolyl, triazolyl,thiazolyl, oxazolyl or oxadiazolyl.

In another embodiment, A is pyrazolyl, thiadiazolyl or —NHC(O)—.

In a further embodiment, A is thiadiazolyl.

In another embodiment, A is pyrazolyl.

In one embodiment, X is O.

In another embodiment, X is —N(C₁-C₆ alkyl)-.

In another embodiment, X is —CH₂—.

In one embodiment, R¹ is C₁-C₆ alkyl, which is optionally substitutedwith a group selected from phenyl, C₃-C₇ cycloalkyl, 5 or 6-memberedmonocyclic heteroaryl and —O—(C₁-C₆ alkyl), wherein said phenyl groupand said 5 or 6-membered monocyclic heteroaryl group can each beoptionally and independently substituted with up to two groups, eachindependently selected from C₁-C₆ alkyl, halo and —O—(C₁-C₆ alkyl).

In another embodiment, R¹ is C₁-C₆ alkyl, which is optionallysubstituted with a group selected from cyclopropyl, phenyl, pyridyl andmethoxy, wherein said phenyl group and said 5 or 6-membered monocyclicheteroaryl group can each be optionally and independently substitutedwith up to 5 groups, each independently selected from methoxy, C₁-C₆alkyl and fluoro.

In another embodiment, R¹ is C₁-C₆ alkyl.

In another embodiment, R¹ is —(C₁-C₆ alkyl)-(C₃-C₇ cycloalkyl).

In still another embodiment, R¹ is ethyl.

In another embodiment, R¹ is isopropyl.

In another embodiment, R¹ is selected from methyl, ethyl, isopropyl,isobutyl, —CH₂CH₂OCH₃, —CH(CH₃) CH₂CH₂OCH₃, para-fluorobenzyl,—CH₂-cyclopropyl and —CH₂-pyridyl.

In one embodiment, R² is H.

In one embodiment, R³ is H.

In another embodiment, R² and R³ are each H.

In one embodiment, R⁴ is H.

In another embodiment, R², R³ and R⁴ are each H.

In one embodiment, R⁵ is H.

In another embodiment, R², R³, R⁴ and R⁵ are each H.

In one embodiment, R⁶ is H.

In another embodiment, R⁶ is —OH.

In one embodiment, R⁷ is H.

In another embodiment, R⁷ is —OH.

In another embodiment, R⁷ is —O—(C₁-C₆ alkyl).

In still another embodiment, R⁷ is methoxy.

In one embodiment, R², R³, R⁴, R⁵ and R⁶ are each H and R⁷ is H, methoxyor —OH.

In another embodiment, R², R³, R⁴, R⁵ and R⁶ are each H and R⁷ ismethoxy.

In another embodiment, R², R³, R⁴, R⁵ and R⁶ are each H, n is 0, and R⁷is methoxy.

In one embodiment, R¹ is C₁-C₆ alkyl; R², R³, R⁴, R⁵ and R⁶ are each H;and R⁷ is H, methoxy or —OH.

In another embodiment, R¹ is ethyl; R², R³, R⁴, R⁵ and R⁶ are each H;and R⁷ is methoxy.

In one embodiment, R⁸ is benzyl, wherein the phenyl moiety of saidbenzyl group can be optionally and independently substituted with up to3 groups, each independently selected from —OR¹¹, C₁-C₆ alkyl and halo.

In another embodiment, R⁸ is benzyl, wherein the phenyl moiety of saidbenzyl group can be optionally and independently substituted with up to3 groups, each independently selected from F, Cl and methyl.

In another embodiment, R⁸ is selected from:

In still another embodiment, R⁸ is C₁-C₆ alkyl.

In another embodiment, R⁸ is methyl.

In one embodiment, X is —CH—; n is 0; and R⁷ is H, methoxy or —OH.

In another embodiment, X is —O—; n is 1; and R⁴, R⁵ and R⁷ are each H.

In one embodiment, (i) R¹ is C₁-C₆ alkyl, which is optionallysubstituted with a group selected from C₃-C₇ cycloalkyl, phenyl, 5 or6-membered monocyclic heteroaryl and —O—(C₁-C₆ alkyl), wherein saidphenyl group and said 5 or 6-membered monocyclic heteroaryl group caneach be optionally and independently substituted with up to two groups,each independently selected from C₁-C₆ alkyl, halo and —O—(C₁-C₆ alkyl),and (ii) R⁸ is benzyl, wherein the phenyl moiety of said benzyl groupcan be optionally and independently substituted with up to 3 groups,each independently selected from —OR¹¹, C₁-C₆ alkyl and halo.

In another embodiment, (i) R¹ is selected from methyl, ethyl, isopropyl,isobutyl, —CH₂CH₂OCH₃, —CH(CH₃) CH₂CH₂OCH₃, para-fluorobenzyl—CH₂-cyclopropyl and —CH₂-pyridyl, and (ii) R⁸ is selected from:

In one embodiment, the Compounds of Formula (I) have Formula (Id):

and pharmaceutically acceptable salts and prodrugs thereof,wherein:

R¹ is C₁-C₆ alkyl; and

R¹⁰ represents up to 3 phenyl group substituents, each independentlyselected from C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) and halo.

In one embodiment, the Compounds of Formula (I) have Formula (Ie):

and pharmaceutically acceptable salts and prodrugs thereof,wherein:

R¹ is C₁-C₆ alkyl, which is optionally substituted with C₃-C₇cycloalkyl, —O—(C₁-C₆ alkyl), C₁-C₆ haloalkyl or phenyl, wherein saidphenyl substituent is optionally substituted with halo;

R² is H or —O—(C₁-C₆ alkyl);

R⁷ is H, C₁-C₆ alkyl or —O—(C₁-C₆ alkyl); and

R¹⁰ represents up to 3 phenyl group substituents, each independentlyselected from C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) and halo.

In one embodiment, for the Compounds of Formula (Ie), R¹ is C₁-C₆ alkyl.

In another embodiment, for the Compounds of Formula (Ie), R¹ is methyl.

In another embodiment, for the Compounds of Formula (Ie), R¹ is ethyl.

In another embodiment, for the Compounds of Formula (Ie), R¹ isisopropyl.

In one embodiment, for the Compounds of Formula (Ie), R² is H.

In one embodiment, for the Compounds of Formula (Ie), R⁷ is H.

In another embodiment, for the Compounds of Formula (Ie), R⁷ is C₁-C₆alkyl.

In another embodiment, for the Compounds of Formula (Ie), R⁷ is—O—(C₁-C₆ alkyl).

In another embodiment, for the Compounds of Formula (Ie), R⁷ is methoxy.

In still another embodiment, for the Compounds of Formula (Ie), R¹ isethoxy.

In one embodiment, for the Compounds of Formula (Ie), each occurrence ofR¹⁰ is halo.

In one embodiment, for the Compounds of Formula (Ie), R¹ is C₁-C₆ alkyl;R² is H, R⁷ is —O—(C₁-C₆ alkyl); and each occurrence of R¹⁰ is halo.

In one embodiment, variables R¹-R¹¹, n, A and X for the Compounds ofFormula (I) are selected independently of each other.

In another embodiment, the Compounds of Formula (I) are in substantiallypurified form.

In one embodiment, the present invention provides the followingCompounds of Formula (I):

or a pharmaceutically acceptable salt thereof.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of aCompound of Formula (I) or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a secondtherapeutic agent selected from the group consisting of HIV antiviralagents, immunomodulators, and anti-infective agents.

(c) The pharmaceutical composition of (b), wherein the HIV antiviralagent is an antiviral selected from the group consisting of HIV proteaseinhibitors, HIV integrase inhibitors, nucleoside reverse transcriptaseinhibitors, CCR5 co-receptor antagonists and non-nucleosidereverse-transcriptase inhibitors.

(d) A pharmaceutical combination that is (i) a Compound of Formula (I)and (ii) a second therapeutic agent selected from the group consistingof HIV antiviral agents, immunomodulators, and anti-infective agents;wherein the Compound of Formula (I) and the second therapeutic agent areeach employed in an amount that renders the combination effective forinhibiting HIV replication, or for treating HIV infection and/orreducing the likelihood or severity of symptoms of HIV infection.

(e) The combination of (d), wherein the HIV antiviral agent is anantiviral selected from the group consisting of HIV protease inhibitors,HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors,CCR5 co-receptor antagonists and non-nucleoside reverse-transcriptaseinhibitors.

(f) A method of inhibiting HIV replication in a subject in need thereofwhich comprises administering to the subject an effective amount of aCompound of Formula (I).

(g) A method of treating HIV infection and/or reducing the likelihood orseverity of symptoms of HIV infection in a subject in need thereof whichcomprises administering to the subject an effective amount of a Compoundof Formula (I).

(h) The method of (g), wherein the Compound of Formula (I) isadministered in combination with an effective amount of at least onesecond therapeutic agent selected from the group consisting of HIVantiviral agents, immunomodulators, and anti-infective agents.

(i) The method of (h), wherein the HIV antiviral agent is an antiviralselected from the group consisting of HIV protease inhibitors, HIVintegrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5co-receptor antagonists and non-nucleoside reverse-transcriptaseinhibitors.

(j) A method of inhibiting HIV replication in a subject in need thereofwhich comprises administering to the subject the pharmaceuticalcomposition of (a), (b) or (c) or the combination of (d) or (e).

(k) A method of treating HIV infection and/or reducing the likelihood orseverity of symptoms of HIV infection in a subject in need thereof whichcomprises administering to the subject the pharmaceutical composition of(a), (b) or (c) or the combination of (d) or (e).

The present invention also includes a compound of the present inventionfor use (i) in, (ii) as a medicament for, or (iii) in the preparation ofa medicament for: (a) medicine, (b) inhibiting HIV replication or (c)treating HIV infection and/or reducing the likelihood or severity ofsymptoms of HIV infection. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moresecond therapeutic agents selected from HIV antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(k) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, aspects, classes, sub-classes, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt orhydrate as appropriate. It is understood that references to compoundswould include the compound in its present form as well as in differentforms, such as polymorphs, solvates and hydrates, as applicable.

It is further to be understood that the embodiments of compositions andmethods provided as (a) through (k) above are understood to include allembodiments of the compounds, including such embodiments as result fromcombinations of embodiments.

The Compounds of Formula (I) may be referred to herein by chemicalstructure and/or by chemical name. In the instance that both thestructure and the name of a Compound of Formula (I) are provided and adiscrepancy is found to exist between the chemical structure and thecorresponding chemical name, it is understood that the chemicalstructure will predominate.

Non-limiting examples of the Compounds of Formula (I) include compounds1-38 as set forth below, and pharmaceutically acceptable salts thereof.

Methods for Making the Compounds of Formula (I)

The Compounds of Formula (I) may be prepared from known or readilyprepared starting materials, following methods known to one skilled inthe art of organic synthesis. Methods useful for making the Compounds ofFormula (I) are set forth in the Examples below and generalized inSchemes A-G, below. Alternative synthetic pathways and analogousstructures will be apparent to those skilled in the art of organicsynthesis. Unless otherwise indicated, all variables are as definedabove.

Scheme A depicts a general method for preparing compounds of the presentinvention wherein a reductive amination between chiral aldehyde 1 andamine 2 provides key amine building block 3. This amine is coupled withcarboxylic acid 4 under standard conditions to provide amide 5. Next,acid-mediated global deprotection concurrently removes three protectinggroups and liberates an intermediate amino alcohol, which is thencyclized under mild basic biphasic conditions to provide diol 6.Mesylation of 6 affords a mixture of mono- and bis-mesylatedintermediate, which is treated with NaOH in situ to affect anintramolecular cyclization to tricyclic morpholine 7. Selectivebromination with NBS followed by amidation under carbonylativeconditions provides penultimate intermediate 9, which is deprotectedunder mild acidic conditions with TFA to provide representativecompounds of the invention of formula 10.

Scheme B depicts a method for preparing compounds in the presentinvention wherein key brominated intermediate 8 is carbonylated in thepresence of CH₃OH to provide ester 11. This ester is saponified tocarboxylic acid 12 under standard conditions and then coupled withhydrazide 13 to provide intermediate 14. Upon treatment with Lawesson'sreagent, 14 cyclizes to the corresponding thiadiazole, which is thendeprotected in situ with TFA to provide representative compounds of theinvention of formula 15.

Scheme C depicts a method for preparing compounds in the presentinvention wherein key brominated intermediate 8 is coupled with arylboronates of the form 16 under Suzuki coupling conditions to provide anintermediate arene product which is deprotected under mild acidicconditions with TFA to provide representative compounds of the inventionof formula 17.

Scheme D depicts a method for preparing compounds in the presentinvention wherein key brominated intermediate 8 is coupled to a TMSalkyne building block under Sonogashia coupling conditions to provideintermediates of the form 19. 19 undergoes a [3+2] cycloaddition withazides of the form 20 to provide N-linked triazoles of the form 21. 21can be readily deprotected under mild acidic conditions with TFA toprovide representative compounds of the invention of formula 22.

Scheme E depicts a general method for preparing compounds of the presentinvention wherein a reductive amination between chiral amine 23 andeither a ketone or an aldehyde provides key amine building block 24.This amine is coupled with carboxylic acid 4 under standard conditionsto provide amide 25. Next, acid-mediated deprotection concurrentlyremoves two protecting groups and facilitates cyclization to providebicyclic ester 26. Mesylation of the primary alcohol of 26 understandard conditions affords intermediate 27, which is then treated withmethylamine under forcing conditions to concurrently displace themesylate intermolecularly followed by intramolecular cyclization of theresulting secondary amine onto the pendant ester to provide tricyclicpiperazinone 28. Selective bromination with NBS followed by amidationunder carbonylative conditions provides penultimate intermediate 30,which is deprotected under mild acidic conditions with TFA to providerepresentative compounds of the invention of formula 31.

Bromide 29 of Scheme E is a valuable common intermediate. It is formedas mixture of enantiomers, but these can be readily separated at thisstage by preparative chiral SFC to provide stable single enantiomersthat can be advanced in this and related chemistries.

Scheme F depicts a general method for preparing compounds of the presentinvention wherein 4-pyrone ester 32 is converted first to thecorresponding benzylic bromide 33, and subsequently to the correspondingphosphonate 34 through an Arbuzov reaction. 34 undergoes an olefinationwith chiral carbonyl compound 35, the product of which is hydrogenatedunder standard conditions, and re-protected to 37. One-pot deprotectionmediated by TFA, followed by thermal cyclization and in situ acylationaffords key bicyclic building block 40. While 38 and 39 can beisolated/characterized and the indicated operations carried outindependently, they are typically carried all the way to the more stable40. Mesylation of the free hydroxyl moiety followed by cyclizationfurnishes key tricyclic building block 42. 42 is then brominatedselectively, and then subjected to carbonylative amidation catalyzed byPd(PPh₃)₄ to provide the penultimate amide intermediate 44. Finally,LiCl-mediated demethylation provides representative compounds of theinvention of formula 45.

Scheme G depicts a general method for preparing compounds of the presentinvention wherein advanced tricyclic intermediate 42 from Scheme F canbe oxidized at the benzylic position in the presence of Davisoxaziridine to provide alcohol 46. Using the a protocol similar to thatdescribed in Scheme F, 46 is brominated, carboxylated, and saponified toprovide carboxylic acid 48. 48 then undergoes a standard amide couplingreaction and then LiCl-mediated demethylation to provide representativecompounds of the invention of formula 50. This indicated sequence ofsteps (carboxylation, saponification, amide coupling) has been typicallyfound to be interchangeable with the more streamlined one-stepcarbonylative amidation highlighted in Scheme F (43 to 44).

Scheme H depicts a general method for preparing compounds of the presentinvention wherein advanced bicyclic intermediate 40 from Scheme F isoxidized to the corresponding aldehyde resulting in the in situcyclization of the pendant amide moiety to furnish hydroxy tricycle 51.This compound is then methylated to furnish 52, and then subsequentlyadvanced through a sequence similar to that shown in Scheme F to furnishmethoxy compounds of the general structure 55.

Scheme I depicts a general method for preparing compounds of the presentinvention wherein advanced tricyclic intermediate 46 from Scheme G ismethylated, and then subsequently advanced through a sequence similar tothat shown in Scheme F to furnish methoxy compounds of the generalstructure 59.

In the methods for preparing compounds of the present invention setforth in the foregoing schemes, functional groups in various moietiesand substituents (in addition to those already explicitly noted in theforegoing schemes) may be sensitive or reactive under the reactionconditions employed and/or in the presence of the reagents employed.Such sensitivity/reactivity can interfere with the progress of thedesired reaction to reduce the yield of the desired product, or possiblyeven preclude its formation. Accordingly, it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. Protection can be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and in T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999, and 2^(nd) edition, 1991. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known in the art. Alternatively the interfering group can beintroduced into the molecule subsequent to the reaction Step of concern.

One skilled in the art of organic synthesis will recognize that thesynthesis of compounds with multiple reactive functional groups, such as—OH and NH₂, may require protection of certain functional groups (i.e.,derivatization for the purpose of chemical compatibility with aparticular reaction condition). Suitable protecting groups for thevarious functional groups of these compounds and methods for theirinstallation and removal are well-known in the art of organic chemistry.A summary of many of these methods can be found in Greene & Wuts,Protecting Groups in Organic Synthesis, John Wiley & Sons, 3^(rd)edition (1999).

One skilled in the art of organic synthesis will also recognize that oneroute for the synthesis of the Compounds of Formula (I) may be moredesirable depending on the choice of appendage substituents.Additionally, one skilled in the relevant art will recognize that insome cases the order of reactions may differ from that presented hereinto avoid functional group incompatibilities and thus adjust thesynthetic route accordingly.

Compounds of formula 10, 15, 17, 22, 31, 45, 50, 55, and 59, and theirindicated intermediates may be further elaborated using methods thatwould be well-known to those skilled in the art of organic synthesis or,for example, the methods described in the Examples below, to make thefull scope of the Compounds of Formula (I).

The starting materials used and the intermediates prepared using themethods set forth in Schemes A-G may be isolated and purified if desiredusing conventional techniques, including but not limited to filtration,distillation, crystallization, chromatography and alike. Such materialscan be characterized using conventional means, including physicalconstants and spectral data.

EXAMPLES General Methods

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention. In these examples, all temperaturesare degrees Celsius unless otherwise noted, and “room temperature”refers to a temperature in a range of from about 20° C. to about 25° C.Mass spectra (MS) were measured by electrospray ion-mass spectroscopy(ESI). ¹H NMR spectra were recorded on Varian or Bruker instruments at400-500 MHz. Compounds described herein were synthesized as racemicmixtures unless otherwise stated in the experimental procedures.

Example 1 Preparation of Intermediate Compounds A and B

Step 1:5-hydroxy-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-4-one

Into a 5-L 4-necked round-bottom flask, purged and maintained with aninert atmosphere of N₂, was placed a solution of5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (225 g, 1.58 mol) in CH₂Cl₂(2 L) and DHP (158 g, 1.88 mol). This was followed by the addition of4-methylbenzene-1-sulfonic acid (2.7 g, 15.68 mmol) at 10° C. Theresulting solution was stirred for 3 h at room temperature. The reactionwas then quenched by the addition of 0.5 N aqueous NaOH (20 mL). Theresulting mixture was washed with brine (200 mL). The organic layer wasseparated and concentrated in vacuo, to provide the title compound (250g) as a yellow solid, which was used in the subsequent step withoutfurther purification.

Step 2:3-hydroxy-2-(hydroxymethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-4-one

Into a 5-L 4-necked round-bottom flask, purged and maintained with aninert atmosphere of N₂, was placed a solution of5-hydroxy-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-4-one (250g, 1.11 mol) in water (1 L), formaldehyde (100 mL) and 1 N aqueous NaOH(1 L). The resulting solution was stirred overnight at room temperature.The pH of the solution was adjusted to pH=5 with AcOH, then extractedwith EtOAc (3×500 mL). The organic layers were combined, dried overNa₂SO₄ and concentrated in vacuo to provide the title compound (310 g,unpurified) as a yellow oil, which was used in the subsequent stepwithout further purification.

Step 3:3-(benzyloxy)-2-(hydroxymethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)-methyl)-4H-pyran-4-one

Into a 2-L 4-necked round-bottom flask, purged and maintained with aninert atmosphere of N₂, was placed a solution3-hydroxy-2-(hydroxymethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-4-one(310 g, 1.21 mol) in DMF (1.2 L), K₂CO₃ (334 g, 2.40 mol) and benzylbromide (217 g, 1.27 mol). The resulting solution was stirred at roomtemperature for 16 h and then poured into water (5 L). The resultingsolution was extracted with of EtOAc (3×1000 mL). The organic layerswere combined, dried over Na₂SO₄ and concentrated under vacuum toprovide the title compound (350 g, 84% over 2 steps) as a yellow oil,which was used in the subsequent step without further purification.

Step 4:3-(benzyloxy)-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxylicacid (Intermediate A)

Into a 10-L 4-necked round-bottom flask, purged and maintained with aninert atmosphere of N₂, was placed a solution of3-(benzyloxy)-2-(hydroxymethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-4-one(350 g, 1.01 mol) in CH₂Cl₂ (3.5 L), TEMPO (3.16 g, 20.22 mmol), a 1 Naqueous solution of KHCO₃ (300 mL), and a solution of potassium bromide(24 g, 201.68 mmol) in water (20 mL). This was followed by the additionof aqueous NaClO (748.6 g, 30%) added dropwise with stirring at 0° C.over 30 min. The resulting solution was stirred overnight at roomtemperature. The reaction mixture was cooled to 5° C. with an ice/saltbath, and the pH adjusted to pH3 with 5% aqueous NaHSO₄. The resultingsolution was extracted with EtOAc (6×500 mL). The organic layers werecombined, dried over Na₂SO₄ and concentrated in vacuo to provideIntermediate Compound A (125 g, 34%) as a white solid.

Step 5: methyl3-(benzyloxy)-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxylate(Intermediate B)

Into a 2-L 4-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed a solution of3-(benzyloxy)-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxylicacid (125 g, 346.9 mmol) in DMF (600 mL), Cs₂CO₃ (226 g, 695.38 mmol),and iodomethane (98.6 g, 694.66 mmol). The resulting solution wasstirred at room temperature for 16 h. Next, it was poured into 2 L ofwater/ice. The solid was collected by filtration and dried in an ovenunder reduced pressure to provide Intermediate Compound B (105 g, 81%)as a yellow solid. LRMS (+ESI) m/z=375. ¹H NMR (400 MHz, CDCl₃): δ7.48-7.44 (2H, d); 7.39-7.29 (3H, m); 6.58 (1H, s); 5.31 (2H, s);4.74-4.72 (1H, d); 4.59-4.54 (1H, d); 4.40-4.35 (1H, d); 3.86-3.78 (4H,m); 3.58-3.54 (1H, m); 1.87-1.65 (6H, m).

Example 2 Preparation of Intermediate Compound C

1-(chloromethyl)-2,4-difluorobenzene (948 mg, 5.8 mL) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (750 mg,3.87 mmol) were combined in DMF (12 mL) at room temperature. SolidCs₂CO₃ (2.5 g, 7.73 mmol) was then added, and the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was filteredthrough a scintered glass funnel, and the filtrate was purified directlyby gradient elution on reverse phase (50×250 mm (5 um) Sunfire Prep C18;27 to 62% CH₃CN/water w/ 0.1% TFA modifier over 30 min at 90 mL/min) toprovide Intermediate Compound C (540 mg, 44%) as an orange oil. LRMS(+ESI) m/z=321.4.

Example 3 Preparation of Intermediate Compound D

Step 1: 2-(2,4-difluorophenyl)acetyl chloride

To a solution of 2-(2,4-difluorophenyl)acetic acid (1.15 g, 6.68 mmol)in CH₂Cl₂ (66.8 mL) was added oxalyl chloride (4.01 mL, 8.02 mmol)followed by 2 drops of DMF. The solution was stirred for 2 h at roomtemperature and then concentrated to dryness in vacuo. The resultingunpurified residue (1.27 g) was used in the subsequent step withoutfurther purification, assuming quantitative conversion.

Step 2: tert-butyl 2-(2-(2,4-difluorophenyl)acetyl)hydrazinecarboxylate

A solution of unpurified 2-(2,4-difluorophenyl)acetyl chloride (0.406 g,2.13 mmol) in CH₂Cl₂ (5 mL) was added dropwise to a stirring solution oftert-butyl hydrazinecarboxylate (0.282 g, 2.130 mmol) and DIEA (0.446ml, 2.56 mmol) in CH₂Cl₂ (21.3 mL). The reaction mixture was stirred for16 h at room temperature, and then washed sequentially with 1 N aqueousHCl (30 mL) and saturated aqueous NaHCO₃ (30 mL). The organic phase wasdried over Na₂SO₄ and concentrated in vacuo, and the resultingunpurified residue (0.564 g) was used in the subsequent step withoutfurther purification.

Step 3: 2-(2,4-difluorophenyl)acetohydrazide hydrochloride

To unpurified tert-butyl2-(2-(2,4-difluorophenyl)acetyl)hydrazinecarboxylate (0.564 g, 1.970mmol) in 1,4-dioxane (19.70 mL) was added a 4 N 1,4-dioxane solution ofHCl (1.72 mL, 6.90 mmol) and stirred for 2 days at room temperature. Thereaction mixture was concentrated in vacuo, and the resultinghydrochloride salt (0.395 g) was used in subsequent chemistry withoutfurther purification. LRMS (+ESI) m/z=187.1.

Example 4 Preparation of Compounds 2 and 3

Step 1: tert-butyl4-((isopropylamino)methyl)-2,2-dimethyloxazolidine-3-carboxylate

To tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (10 g, 43.6mmol) in CH₃OH (87 mL) was added isopropylamine (14.86 mL, 174 mmol).The resulting mixture was stirred at 50° C. for 16 h. The mixture wascooled to room temperature and NaBH₄ (4.95 g, 131 mmol) was added. Theresulting mixture was stirred at room temperature for 1 hour. Saturatedaqueous NaHCO₃ (100 mL) was added and the slurry was extracted with ˜4:1CH₂Cl₂/EtOH (2×500 mL). The organics were combined and concentrated toprovide the title compound (11.9 g, 99%) as a pale yellow oil. LRMS(+ESI) m/z=273.5.

Step 2: tert-butyl4-((3-(benzyloxy)-N-isopropyl-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate

A solution of tert-butyl4-((isopropylamino)methyl)-2,2-dimethyloxazolidine-3-carboxylate (10 g,36.7 mmol) and Intermediate A (12.4 g, 34.4 mmol) in DMF (68.8 mL) wastreated with HATU (14.39 g, 37.9 mmol) then DIEA (18.03 mL, 103 mmol).The mixture was stirred at room temperature for 10 min and thenpartitioned between water (300 mL) and EtOAc (500 mL). The organic phasewas washed with water (2×300 mL) and brine (1×200 mL), and then driedover Na₂SO₄, filtered, then concentrated in vacuo. The resulting residue(˜24 g) was used in the subsequent step without further purification.LRMS (+ESI) m/z=615.4.

Step 3:9-(benzyloxy)-4,6-bis(hydroxymethyl)-2-isopropyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione

A solution of tert-butyl4-((3-(benzyloxy)-N-isopropyl-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate(21.2 g, 34.5 mmol) in CH₃OH (86 mL) was treated with concentrated HCl(7.18 mL, 86 mmol) and stirred at 70° C. for 30 min. The mixture wasconcentrated in vacuo and the residue suspended in CH₂Cl₂ (100 mL),treated with saturated aqueous NaHCO₃ (100 mL), stirred vigorously for20 min, and the layers were then separated. The aqueous phase wasback-extracted with ˜4:1 CH₂Cl₂/EtOH (3×500 mL). The organic layers werecombined and concentrated in vacuo to provide the title compound (12.8g) as a tan foam, which was used in the subsequent step without furtherpurification. LRMS (+ESI) m/z=373.3.

Step 4:7-(benzyloxy)-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dione

A solution of9-(benzyloxy)-4,6-bis(hydroxymethyl)-2-isopropyl-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione(12.8 g, 34.4 mmol) in DMF (344 mL) was treated with TEA (9.58 mL, 68.7mmol) and cooled to 0° C. The mixture was treated with methanesulfonicanhydride (5.99 g, 34.4 mmol) and was stirred at 0° C. for 20 min. Themixture was treated with 1 N aqueous NaOH (172 mL, 172 mmol) and stirredat 0° C. for 20 min. Next, the reaction mixture was extracted withCH₂Cl₂ (400 mL). The aqueous phase was back-extracted with a ˜4:1mixture of CH₂Cl₂:EtOH (2×500 mL). The organic phases were combined andthe total volume reduced to ˜250 mL (primarily DMF), and the resultingsolution was carried on to the subsequent step without furtherpurification assuming quantitative conversion. LRMS (+ESI) m/z=355.2.

Step 5: (S) and(R)-7-(benzyloxy)-9-bromo-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dione

A solution of unpurified7-(benzyloxy)-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dionein ˜250 mL DMF (12 g, 33.9 mmol) from the previous step was diluted withDCM (100 mL, 0.1 M total concentration), treated with NB S (9.04 g, 50.8mmol), and stirred at room temperature for 10 min. The mixture wasconcentrated and partitioned between water (300 mL) and EtOAc (400 mL).The aqueous phase was back-extracted with EtOAc (400 mL) and then withCH₂Cl₂ (400 mL). The combined organic phases were dried over Na₂SO₄,filtered, and concentrated in vacuo. The resulting residue was purifiedby gradient elution on silica gel (RediSep-Rf-330 g, 0 to 100% [10% MeOHin CH₂Cl₂]/CH₂Cl₂, 35 minute gradient) to provide the title racemiccompound as an orange oil (6.8 g, 45.6% over 4 steps, ˜80% pure). LRMS(+ESI) m/z=433.3. ¹H NMR (500 MHz, CDCl₃): δ 7.70 (d, J=7.4 Hz, 2H);7.33-7.35 (m, 3H); 5.34 (d, J=9.4 Hz, 1H); 5.04 (d, J=9.4 Hz, 1H); 4.94(d, J=16.7 Hz, 1H); 4.80-4.82 (m, 1H); 4.71 (d, J=16.8 Hz, 1H);4.01-4.07 (m, 2H); 3.74 (t, J=11.3 Hz, 1H); 3.31 (t, J=12.8 Hz, 1H);2.96-2.98 (m, 1H); 1.13 (d, J=6.7 Hz, 3H); 0.99 (d, J=6.9 Hz, 3H).

Enantiomers were separated by chiral preparative SFC (2-cm×25-cm OD-Hcolumn; isocratic [50% (0.1% DEA/CH₃OH)]/[50% CO₂]; 50 mL/min flowrate;220 nm) to provide (S) and(R)-7-(benzyloxy)-9-bromo-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dionesas tan solids. The second eluting enantiomer was determined to be theenantiomer of interest.

Step 6:(R)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxamide

A suspension of(R)-7-(benzyloxy)-9-bromo-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dione(200 mg, 0.462 mmol), DIEA (0.403 mL, 2.308 mmol),(2,4-difluorophenyl)methanamine (264 mg, 1.846 mmol), and Pd(PPh₃)₄ (213mg, 0.185 mmol) in DMSO (15.4 mL) was degassed with a stream of N₂, theflask was evacuated, and back-filled three times with CO_((g)). Thereaction mixture was stirred under a CO_((g)) atmosphere (balloon) at100° C. for 16 hours. The mixture was partitioned between water (50 mL)and EtOAc (50 mL). The organic phase was washed with water (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered, and in vacuo. The resultingresidue was purified by gradient elution on reverse phase (30×150 mm (5um) Sunfire Prep C18; 5 to 95% CH₃CN/water w/ 0.1% TFA modifier over 20min at 40 mL/min) to provide the title compound (167 mg, 69%) as a tanfoam. LRMS (+ESI) m/z=524.3. ¹H NMR (500 MHz, CDCl₃): δ 11.03 (s, 1H);7.61 (d, J=7.4 Hz, 2H); 7.33-7.35 (m, 4H); 6.81-6.83 (m, 2H); 5.73 (d,J=18.4 Hz, 1H); 5.40 (d, J=9.9 Hz, 1H); 5.17-5.18 (m, 2H); 4.88-4.89 (m,1H); 4.58-4.60 (m, 2H); 4.21-4.24 (m, 2H); 3.59 (t, J=11.0 Hz, 1H);3.28-3.30 (m, 1H); 3.12 (t, J=12.4 Hz, 1H); 1.22 (d, J=6.6 Hz, 3H); 1.15(d, J=6.9 Hz, 3H).

Step 7:(R)—N-(2,4-difluorobenzyl)-7-hydroxy-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxamide(Compound 3)

A solution of(R)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxamide(167 mg, 0.319 mmol) in TFA (1.5 mL, 19.47 mmol) was heated to 60° C.and stirred for 10 min. The mixture was concentrated in vacuo andpurified directly by gradient elution on reverse phase (30×150 mm (5 um)Sunfire Prep C18; 5 to 95% CH₃CN/water w/ 0.1% TFA modifier over 20 minat 40 mL/min) to provide compound 2 (83.8 mg, 60.6%) as an off-whitecrystalline solid. LRMS (+ESI) m/z=434.2. ¹H NMR (400 MHz, CDCl₃): δ10.71 (s, 1H); 7.36 (q, J=7.8 Hz, 1H); 6.78-6.81 (m, 2H); 5.52 (d,J=17.9 Hz, 1H); 5.09 (d, J=17.9 Hz, 1H); 4.92-4.94 (m, 1H); 4.56 (bm,2H); 4.24-4.27 (m, 2H); 3.72 (t, J=10.7 Hz, 1H); 3.40-3.42 (m, 2H); 1.26(d, J=6.8 Hz, 3H); 1.23 (d, J=6.8 Hz, 3H).

Racemic7-(benzyloxy)-9-bromo-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dionewas also carried forth according to the methods described in above toprovide racemic compound 2:

Example 5 Preparation of Compound 13

Step 1: methyl7-(benzyloxy)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxylate

A suspension of7-(benzyloxy)-9-bromo-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dione(Example 4, 100 mg, 0.231 mmol), DIEA (202 μl, 1.154 mmol), andPd(PPh₃)₄ (107 mg, 0.092 mmol) in DMSO (5770 μl) and CH₃OH (1923 μl) wasdegassed with N₂ for 2 min. Next, the flask was evacuated andback-filled with three times with CO_((g)). The reaction mixture washeated to 90° C. and stirred under an atmosphere of CO_((g)) (balloon)for 16 hours. The mixture was filtered through a syringe filter and thefiltrate was purified directly by gradient elution on reverse phase(30×150 mm (5 um) Sunfire Prep C18; 5 to 95% CH₃CN/water w/ 0.1% TFAmodifier over 20 min at 40 mL/min) to provide the title compound (14 mg,14.7%) as a yellow film. LRMS (+ESI) m/z=413.2.

Step 2:7-(benzyloxy)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxylicacid

To a solution of methyl7-(benzyloxy)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxylate(14 mg, 0.034 mmol) in THF (226 μl), CH₃OH (56.6 μl), and water (56.6μl) was added lithium hydroxide monohydrate (1.42 mg, 0.034 mmol). Thereaction mixture was stirred for 1 hour at room temperature. Next, thereaction mixture was neutralized with 1 N HCl, concentrated in vacuo,and used in the subsequent step without further purification, assumingquantitative conversion. LRMS (+ESI) m/z=399.2.

Step 3:7-(benzyloxy)-N′-(2-(2,4-difluorophenyl)acetyl)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carbohydrazide

To a solution of unpurified7-(benzyloxy)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carboxylicacid (13.5 mg, 0.034 mmol) in DMF (339 μl) was added2-(2,4-difluorophenyl)acetohydrazide hydrochloride (9.05 mg, 0.041mmol), DIEA (23.67 μl, 0.136 mmol), and HATU (14.17 mg, 0.037 mmol). Thesolution was stirred for 10 min at room temperature, and then purifieddirectly by gradient elution on reverse phase (30×150 mm (5 μm) SunfirePrep C18; 5 to 95% CH₃CN/water w/ 0.1% TFA modifier over 20 min at 40mL/min) to provide the title compound (8.5 mg, 44.3%) as a pale yellowfilm. LRMS (+ESI) m/z=567.3. ¹H NMR (400 MHz, CDCl₃): δ 12.92 (s, 1H);8.63 (s, 1H); 7.62 (d, J=7.2 Hz, 2H); 7.25-7.40 (m, 4H); 6.80-6.85 (m,2H); 5.61 (d, J=18.0 Hz, 1H); 5.23 (d, J=9.4 Hz, 1H); 5.05-5.08 (m, 2H);4.76-4.79 (m, 1H); 4.02-4.09 (m, 2H); 3.63 (s, 2H); 3.55 (t, J=11.1 Hz,1H); 3.21 (t, J=12.5 Hz, 1H); 2.94 (d, J=13.7 Hz, 1H); 1.12 (d, J=6.6Hz, 3H); 1.06 (d, J=6.9 Hz, 3H).

Step 4:9-(5-(2,4-difluorobenzyl)-1,3,4-thiadiazol-2-yl)-7-hydroxy-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dione

A solution of7-(benzyloxy)-N′-(2-(2,4-difluorophenyl)acetyl)-5-isopropyl-6,8-dioxo-3,3a,4,5,6,8-hexahydro-1H-2-oxa-3a1,5-diazaphenalene-9-carbohydrazide(8.4 mg, 0.015 mmol) in THF (148 μl) was treated with Lawesson's Reagent(6.60 mg, 0.016 mmol) and stirred at 60° C. overnight. The reactionmixture was concentrated in vacuo, treated with TFA (228 μl, 2.97 mmol),and stirred at 60° C. for 15 minutes. The reaction mixture was againconcentrated in vacuo and then purified by gradient elution on reversephase (30×150 mm (5 um) Sunfire Prep C18; 5 to 95% CH₃CN/water w/ 0.1%TFA modifier over 20 min at 40 mL/min) to provide compound 13 (5.5 mg,75%) as a tan solid. LRMS (+ESI) m/z=475.2. ¹H NMR (500 MHz, CDCl₃): δ7.34 (d, J=7.8 Hz, 1H); 6.83-6.85 (m, 2H); 5.67 (d, J=18.2 Hz, 1H); 5.20(d, J=18.2 Hz, 1H); 4.98 (t, J=7.0 Hz, 1H); 4.44 (s, 2H); 4.31 (t,J=15.1 Hz, 2H); 3.84 (t, J=10.3 Hz, 1H); 3.44-3.47 (m, 2H); 1.29 (d,J=7.0 Hz, 3H); 1.25 (d, J=6.5 Hz, 3H).

Example 6 Preparation of Compound 14

A suspension of7-(benzyloxy)-9-bromo-5-isopropyl-3,3a,4,5-tetrahydro-1H-2-oxa-3a1,5-diazaphenalene-6,8-dione(Example 4, 15 mg, 0.035 mmol),1-(2,4-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(22.17 mg, 0.069 mmol), Pd(PPh₃)₄ (4.00 mg, 3.46 μmol) and Cs₂CO₃ (22.56mg, 0.069 mmol) in THF (700 μl) and water (70 μl) was degassed under astream of N₂ for 1 min, sealed in a pressure vial, and stirred at 110°C. for 16 hours. Next, the mixture was cooled to room temperature andtreated with TFA (500 μl), heated to 60° C., and stirred for 10 min. Themixture was concentrated and purified directly by gradient elution onreverse phase (30×150 mm (5 μm) Sunfire Prep C18; 5 to 95% CH₃CN/waterw/ 0.1% TFA modifier over 20 min at 40 mL/min) to provide compound 14(8.2 g, 52%) as a tan film. LRMS (+ESI) m/z=457.2. ¹H NMR (500 MHz,CDCl₃): δ 8.00 (s, 1H); 7.46 (s, 1H); 7.38-7.40 (m, 1H); 6.82-6.90 (m,2H); 5.35 (dd, J=19.7, 15.5 Hz, 2H); 4.97-4.98 (m, 1H); 4.86 (d, J=15.7Hz, 1H); 4.68 (d, J=15.6 Hz, 1H); 4.27 (dd, J=11.8, 4.5 Hz, 1H);4.19-4.21 (m, 1H); 3.75 (t, J=10.9 Hz, 1H); 3.40 (d, J=7.5 Hz, 2H); 1.25(d, J=6.9 Hz, 3H); 1.23 (d, J=6.9 Hz, 3H).

Example 7 Preparation of Compound 16

Step 1: tert-butyl2-((tert-butoxycarbonyl)amino)-3-(isopropylamino)propanoate

To tert-butyl 3-amino-2-((tert-butoxycarbonyl)amino)propanoatehydrochloride (16.9 mmol, 5 g) in CH₃OH (33.7 mL) was added acetone (84mmol, 6.2 mL). The resulting mixture was stirred at 50° C. for 16 h. Themixture was cooled to room temperature and NaBH₄ (51 mmol, 1.9 g) wasadded. The resulting mixture was stirred at room temperature for 1 hour.Saturated aqeuous NaHCO₃ was added (50 mL) and the mixture was extractedwith CH₂Cl₂ (3×200 mL). The organics were combined and concentrated invacuo to provide the title compound (5.1 g, 100%) as a colorless oil.LRMS (+ESI) m/z=303.2. 1H NMR (499 MHz, DMSO): δ 6.98 (d, J=8.0 Hz, 1H);3.92 (d, J=7.5 Hz, 1H); 2.74 (d, J=5.9 Hz, 2H); 2.64 (t, J=7.7 Hz, 1H);1.39 (app s, 18H); 0.93 (d, J=6.0 Hz, 3H); 0.94 (d, J=6.0 Hz, 3H).

Step 2: tert-butyl3-(3-(benzyloxy)-N-isopropyl-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxamido)-2-((tert-butoxycarbonyl)amino)propanoate

To tert-butyl2-((tert-butoxycarbonyl)amino)-3-(isopropylamino)propanoate (17 mmol,5.1 g) in DMF (43.5 mL) was added Intermediate A (13 mmol, 3.6 g)followed by DIEA (39.1 mmol, 6.8 mL) and HATU (19.6 mmol, 7.4 g). Theresulting mixture was stirred at room temperature for 10 min. Thereaction mixture was diluted with EtOAc (600 mL) and washed sequentiallywith saturated aqueous NaHCO₃ (200 mL) and water (3×200 mL), and theorganic layer was separated. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by gradientelution on SiO₂ (330 g SiO₂, 0 to 100% EtOAc in hexanes) to provide thetitle compound (6.5 g, 77%) as a yellow gum. LRMS (+ESI) m/z=645.4.

Step 3: tert-butyl9-(benzyloxy)-6-(hydroxymethyl)-2-isopropyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrazine-4-carboxylate

To tert-butyl3-(3-(benzyloxy)-N-isopropyl-4-oxo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4H-pyran-2-carboxamido)-2-((tert-butoxycarbonyl)amino)propanoate(4.9 mmol, 3.5 g) in a 95:5 mixture of CH₃CN/water (245 mL) was addedconcentrated TFA (150 mmol, 11.3 mL). The resulting mixture was stirredat 70° C. for 5 hours. The mixture was cooled to room temperature anddiluted with CH₂Cl₂ (600 mL). The organic layer was carefullyneutralized with saturated aqueous NaHCO₃, washed sequentially withsaturated aqueous NaHCO₃ (200 mL) and water (200 mL), and the organiclayer was then separated. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo to provide the title compound (1.6 g,73%) as a pale yellow foam which was carried on to the subsequent stepwithout further purification. LRMS (+ESI) m/z=443.3.

Step 4: tert-butyl9-(benzyloxy)-2-isopropyl-6-(((methylsulfonyl)oxy)methyl)-1,8-dioxo-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrazine-4-carboxylate

To tert-butyl9-(benzyloxy)-6-(hydroxymethyl)-2-isopropyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrazine-4-carboxylate(3.4 mmol, 1.5 g) in CH₂Cl₂ (17 mL) cooled to 0° C. was added TEA (8.5mmol, 1.2 mL) followed by methanesulfonylchloride (4 mmol, 0.3 mL). Theresulting mixture was warmed to room temperature and stirred for 5 min.The mixture was diluted with CH₂Cl₂ (150 mL), washed sequentially withsaturated aqueous NaHCO₃ (35 mL) and water (35 mL), and the organiclayer was separated. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo to provide the title compound (1.7 g, 99%) asa pale yellow foam which was carried on to the subsequent step withoutfurther purification. LRMS (+ESI) m/z=521.3.

Step 5:9-(benzyloxy)-2-isopropyl-5-methyl-3,3a,5,6-tetrahydro-2,3a1,5-triazaphenalene-1,4,8(2H)-trione

To tert-butyl9-(benzyloxy)-2-isopropyl-6-(((methylsulfonyl)oxy)methyl)-1,8-dioxo-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrazine-4-carboxylate(3.3 mmol, 1.7 g) in DMF (17 mL) was added methylamine hydrochloride (5mmol, 340 mg) followed by TEA (10 mmol, 1.4 mL). The resulting mixturewas stirred at 70° C. for 2 h. The temperature was then increased to140° C. and the mixture stirred at that temperature for 16 h. Themixture was cooled to room temperature, diluted with CH₂Cl₂ (150 mL),washed sequentially with saturated aqueous NaHCO₃ (35 mL) and water (35mL), and the organic layer was separated. The organic layer was driedover MgSO₄, filtered and concentrated in vacuo to provide the titlecompound (1 g, 79%) as a brown foam which was carried on to thesubsequent step without further purification. LRMS (+ESI) m/z=382.3.

Step 6:9-(benzyloxy)-7-bromo-2-isopropyl-5-methyl-3,3a,5,6-tetrahydro-2,3a1,5-triazaphenalene-1,4,8(2H)-trione

To9-(benzyloxy)-2-isopropyl-5-methyl-3,3a,5,6-tetrahydro-2,3a1,5-triazaphenalene-1,4,8(2H)-trione(0.1 mmol, 40 mg) in CH₂Cl₂ (1 mL) was added NBS (0.1 mmol, 21 mg). Theresulting mixture was stirred at room temperature for 5 minutes. Themixture was purified directly by gradient elution on SiO₂ (4 g SiO₂, 0to 15% CH₃OH in CH₂Cl₂) to provide the title compound (44 mg, 91%) as ayellow solid. LRMS (+ESI) m/z=462.1. 1H NMR (500 MHz, CDCl₃): δ 7.60 (d,J=7.3 Hz, 2H); 7.32 (dt, J=14.3, 7.2 Hz, 3H); 5.35 (d, J=9.9 Hz, 1H);5.10 (d, J=9.8 Hz, 1H); 4.88-4.90 (m, 1H); 4.77 (d, J=17.2 Hz, 1H); 4.54(t, J=16.0 Hz, 2H); 4.07 (dd, J=14.3, 3.4 Hz, 1H); 3.50 (t, J=13.0 Hz,1H); 3.08 (s, 3H); 1.23 (d, J=6.8 Hz, 3H); 1.20 (d, J=6.8 Hz, 3H).

Step 7:9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-isopropyl-5-methyl-1,4,8-trioxo-1,2,3,3a,4,5,6,8-octahydro-2,3a1,5-triazaphenalene-7-carboxamide

To9-(benzyloxy)-7-bromo-2-isopropyl-5-methyl-3,3a,5,6-tetrahydro-2,3a1,5-triazaphenalene-1,4,8(2H)-trione(0.1 mmol, 42 mg) in DMSO (3 mL) was added 2,4-difluorobenzylamine (0.4mmol, 52 mg), DIEA (0.5 mmol, 80 μL) and Pd(PPh₃)₄ (0.04 mmol, 42 mg)under nitrogen. The resulting mixture was evacuated and purged threetimes with CO_((g)) and stirred at 100° C. under a CO_((g)) atmosphere(balloon) overnight. The mixture was concentrated under a stream ofnitrogen to remove volatiles and then purified directly by reverse phasechromatography (SunFire™ Prep C18 OBD™ 5 μm 30×150 mm column; 10 to 70%CH₃CN/water with 0.1% TFA modifier over 20 min) to provide the titlecompound (22 mg, 44%) as a white solid. LRMS (+ESI) m/z=551.3.

Step 8:N-(2,4-difluorobenzyl)-9-hydroxy-2-isopropyl-5-methyl-1,4,8-trioxo-1,2,3,3a,4,5,6,8-octahydro-2,3a1,5-triazaphenalene-7-carboxamide

To9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-isopropyl-5-methyl-1,4,8-trioxo-1,2,3,3a,4,5,6,8-octahydro-2,3a1,5-triazaphenalene-7-carboxamide(0.04 mmol, 22 mg) in CH₂Cl₂ (1 mL) was added concentrated TFA (6.5mmol, 500 μL). The resulting mixture was stirred at room temperature for2 hours. The mixture was concentrated under a stream of N₂ to removevolatiles and then purified by reverse phase chromatography (SunFire™Prep C18 OBD™ 5 μm 30×150 mm column; 10 to 70% CH₃CN/water with 0.1% TFAmodifier over 20 minutes) to provide compound 16 (8 mg, 43%) as a whitesolid. LRMS (+ESI) m/z=461.2. 1H NMR (500 MHz, CDCl₃): δ 10.79 (s, 1H);7.36 (q, J=7.6 Hz, 1H); 6.81-6.84 (m, 2H); 5.96 (d, J=19.3 Hz, 1H);4.92-4.93 (m, 1H); 4.83 (d, J=19.3 Hz, 1H); 4.61 (t, J=13.6 Hz, 3H);4.29 (dd, J=14.2, 4.0 Hz, 1H); 3.57 (dd, J=14.2, 12.0 Hz, 1H); 3.17 (s,3H); 1.31 (d, J=6.8 Hz, 3H); 1.27 (d, J=6.8 Hz, 3H).

Example 8 Preparation of Compound 17

Step 1: methyl3-(benzyloxy)-6-(hydroxymethyl)-4-oxo-4H-pyran-2-carboxylate

3-(benzyloxy)-6-((methoxymethoxy)methyl)-4-oxo-4H-pyran-2-carboxylicacid was prepared according to the synthetic route outlined in U.S. Pat.No. 7,211,572 (S. Miyazaki, inventor; 2007 May 1). Intermediate CompoundA from Example 1 can be used interchangeably with this starting materialin the subsequent chemistry.

To a solution of3-(benzyloxy)-6-((methoxymethoxy)methyl)-4-oxo-4H-pyran-2-carboxylicacid (4.0 g, 12.5 mmol) in CH₃OH (35 mL) was added 4 N HCl in CH₃OH (35mL) at 0° C. The resulting mixture was stirred at room temperature for 6h. The reaction mixture was concentrated in vacuo, diluted with water(50 mL), extracted with EtOAc (3×100 mL), dried over Na₂SO₄, and theorganic phase concentrated in vacuo to provide the title compound (3.0g, 83%) which was carried on to the subsequent step without furtherpurification. LRMS (+ESI) m/z: 291.1. ¹H NMR (400 MHz, CDCl₃) δ7.45-7.43 (m, 1H); 7.38-7.34 (m, 4H); 6.61 (s, 1H); 5.28 (s, 2H); 4.53(s, 2H); 3.86 (s, 3H).

Step 2: methyl3-(benzyloxy)-6-(((methylsulfonyl)oxy)methyl)-4-oxo-4H-pyran-2-carboxylate

To a stirred solution of methyl3-(benzyloxy)-6-(hydroxymethyl)-4-oxo-4H-pyran-2-carboxylate (5 g, 17.2mmol) in CH₂Cl₂ (100 mL) was added TEA (4.6 mL, 34.4 mmol) andmethanesulfonyl chloride (2.1 mL, 25.8 mmol) at 0° C. After stirring for2 h at room temperature, the mixture was diluted with CH₂Cl₂ (50 mL) andwashed with brine (30 mL). The organic layer was dried over Na₂SO₄, andconcentrated to provide the title compound (5.3 g, 84%) which wascarried on to the subsequent step without further purification. LRMS(+ESI) m/z: 369.1.

Step 3: methyl3-(benzyloxy)-6-(bromomethyl)-4-oxo-4H-pyran-2-carboxylate

To a stirred solution of methyl3-(benzyloxy)-6-(((methylsulfonyl)oxy)-methyl)-4-oxo-4H-pyran-2-carboxylate(5.3 g, 14.4 mmol) in DMF (35 mL) was added NaBr (2.9 g, 28.8 mmol) atroom temperature. After further stirring for 50 min, the reactionmixture was poured into water (100 mL) and extracted by EtOAc (3×100mL). The organic layer was dried over Na₂SO₄, and concentrated in vacuo.The residue was purified by gradient elution on SiO₂ (200 g SiO₂, 0 to10% EtOAc in hexanes) to provide the title compound (4 g, 81%). LRMS(+ESI) m/z: 354.0. ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.46 (m, 2H);7.34-7.36 (m, 3H); 6.53 (s, 1H); 5.30 (s, 2H); 4.19 (s, 2H); 3.80 (s,3H).

Step 4: methyl3-(benzyloxy)-6-((dimethoxyphosphoryl)methyl)-4-oxo-4H-pyran-2-carboxylate

To a solution of methyl3-(benzyloxy)-6-(bromomethyl)-4-oxo-4H-pyran-2-carboxylate (4 g, 11.2mmol) in toluene (100 mL) was added trimethyl phosphite (10 mL, 112mmol) and the mixture was heated to reflux for 86 h. Excess trimethylphosphite was removed by distillation and the resulting oily residue waspurified by gradient elution on SiO₂ (180 g SiO₂, 50% to 10% EtOAc inhexanes) to provide the title compound (3.4 g, 79%) as a yellow oil.LRMS (+ESI) m/z: 383.1. ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.46 (m, 2H);7.32-7.35 (m, 3H); 6.43 (s, 1H); 5.29 (s, 2H); 3.80 (s, 3H); 3.78 (s,6H); 3.10 (s, 2H).

Step 5: tert-butyl4-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-2,2-dimethyloxazolidine-3-carboxylate

To solution of methyl3-(benzyloxy)-6-((dimethoxyphosphoryl)methyl)-4-oxo-4H-pyran-2-carboxylate(500 mg, 1.30 mmol) in THF (5 mL) was added a 1.88 M THF solution of LDA(0.8 mL, 1.50 mmol) under N₂ and then the mixture was stirred at −78° C.for 30 min. Then tert-butyl4-formyl-2,2-dimethyloxazolidine-3-carboxylate (300 mg, 1.30 mmol) inTHF (5 mL) was added and the mixture was stirred at the same temperaturefor 2 h. The mixture was quenched by addition of aqueous 1 N HCl andconcentrated to dryness in vacuo. The residue was purified by gradientelution on SiO₂ (10 g SiO₂, 0% to 30% EtOAc in hexanes) to provide thetitle compound (358 mg, 58%) as a yellow oil. LRMS (+ESI) m/z: 486.2. ¹HNMR (400 MHz, CDCl₃) δ 7.45-7.47 (m, 2H); 7.30-7.37 (m, 3H); 6.59-6.66(m, 1H); 6.31 (s, 1H); 6.1-56.27 (m, 2H); 5.31 (s, 2H); 4.44-4.57 (m,3H); 4.08-4.15 (m, 1H); 3.87 (s, 1H); 1.42-1.66 (m, 15H).

Step 6: tert-butyl4-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate

A mixture of (E)-tert-butyl4-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-2,2-dimethyloxazolidine-3-carboxylate(485 mg, 1.0 mmol) and 10% Pd(OH)₂ on carbon (100 mg) in THF (2 mL) wasstirred at room temperature under an atmosphere of H₂ (balloon) for 20min. The mixture was filtered and the filtrate was concentrated in vacuoto provide the title compound (350 mg, 95%), which was carried on to thesubsequent step without further purification. LRMS (+ESI) m/z: 398.2.

Step 7: tert-butyl4-(2-(5-methoxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate

A mixture of tert-butyl4-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate(500 mg, 2.60 mmol) in 1:1 CH₂Cl₂/CH₃OH (10 mL) and TMSCH₂N₂ (5 mL, 10.0mmol) was stirred at room temperature for 2 h. The reaction mixture wasdissolved in water (30 mL) and extracted with EtOAc (3×20 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresulting residue was purified by gradient elution on SiO₂ (10 g SiO₂,0% to 20% EtOAc in hexanes) to provide the title compound (420 mg, 81%)as a solid. LRMS (+ESI) m/z: 412.2. ¹H NMR (400 MHz, CDCl₃) δ 6.29-6.33(m, 1H); 3.98 (s, 3H); 3.89 (s, 3H); 3.72-3.81 (m, 3H); 2.54-2.61 (m,2H); 1.9-22.08 (m, 2H); 1.65 (s, 9H); 1.43 (s, 6H).

Step 8:N-(4-fluorobenzyl)-3-(hydroxymethyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizine-5-carboxamide

To a mixture of tert-butyl4-(2-(5-methoxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate(500 mg, 1.21 mmol) in CH₂Cl₂ (25 mL) was added TFA (6 mL) at 0° C. Thenthe mixture was stirred at the room temperature for 2 h, concentratedunder reduced pressure, and carried on to the subsequent step withoutfurther purification. MS (+ESI) m/z: 272.1.

A solution of unpurified methyl6-(3-amino-4-hydroxybutyl)-3-methoxy-4-oxo-4H-pyran-2-carboxylate (320mg, 1.21 mmol) in EtOH (15 mL) was heated to reflux for 2 h,concentrated under reduced pressure, and carried on to the subsequentstep without further purification. MS (+ESI) m/z: 282.3.

To a solution of crude 7-ethoxy-3-(hydroxymethyl)-6-methoxy-5-(methoxycarbonyl)-2,3-dihydro-1H-indolizin-4-ium (300 mg, 1.12 mmol) in EtOH (5mL) was added (4-fluorophenyl)methanamine (423 mg, 3.6 mmol) and themixture was irradiated in a microwave reactor at 80° C. for 30 min. Thereaction mixture was concentrated in vacuo and the mixture was purifieddirectly by reverse phase chromatography (Synergi™ Max-RP C18 4 μm30×150 mm column; 1 to 25% CH₃CN/water with 0.075% TFA modifier over 8minutes) to provide the title compound (300 mg, 72% over 3 steps) as ayellow oil. LRMS (+ESI) m/z: 347.1. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s,1H); 7.44-7.48 (m, 2H); 7.01-7.09 (m, 2H); 6.67 (m, 1H); 4.88 (s, 1H);4.51-4.64 (m, 2H); 3.80 (s, 3H); 3.65-3.78 (m, 2H); 2.88-3.01 (m, 2H);2.29-2.46 (m, 2H).

Step 9:(5-((4-fluorobenzyl)carbamoyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizin-3-yl)methyl methanesulfonate

To a solution ofN-(4-fluorobenzyl)-3-(hydroxymethyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizine-5-carboxamide(300 mg, 0.87 mmol) in CH₂Cl₂ (5 mL) was added TEA (263 mg, 2.6 mmol)and MsCl (171 mg, 1.5 mmol). The resulting mixture was stirred at theroom temperature for 2 h. Next, water (10 mL) was added, the mixture wasextracted with CH₂Cl₂ (3×20 mL), and then concentrated in vacuo toprovide the title compound (360 mg, 91%), which was carried on to thesubsequent step without further purification. LRMS (+ESI) m/z: 425.1.

Step 10:(5-((4-fluorobenzyl)carbamoyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizin-3-yl)methyl methanesulfonate

A mixture of Cs₂CO₃ (530 mg, 1.5 mmol) in DMF (5 mL) was stirred at 105°C. for 30 min. Next,(5-((4-fluorobenzyl)carbamoyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizin-3-yl)methylmethanesulfonate (220 mg, 0.54 mmol) in DMF (3 mL) was added dropwise,and the mixture was stirred for 2 h. The mixture was cooled to roomtemperature, water (10 mL) was added, and the reaction mixture wasextracted with CH₂Cl₂ (4×20 mL), and concentrated in vacuo. Theresulting residue was purified by preparative thin layer chromatography(CH₂Cl₂/MeOH=10:1) to provide the title compound (100 mg, 58%) as ayellow oil. LRMS (+ESI) m/z: 329.1. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.33(m, 2H); 7.04-7.08 (m, 2H); 6.92 (s, 1H); 5.00 (s, 1H); 4.43-4.47 (m,2H); 3.71 (s, 3H); 3.56-3.70 (m, 2H); 3.12-3.16 (m, 2H); 2.45-2.47 (m,1H); 1.94-2.00 (m, 1H).

Step 11:6-bromo-2-(4-fluorobenzyl)-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

To a solution of(5-((4-fluorobenzyl)carbamoyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizin-3-yl)methylmethanesulfonate (100 mg, 0.303 mmol) in CH₂Cl₂ (10 mL) was addedanhydrous NBS (179 mg, 1.0 mmol). The mixture was stirred at roomtemperature for 2 hours. The resulting residue was purified bypreparative thin layer chromatography (CH₂Cl₂/CH₃OH=10:1) to provide thetitle compound (100 mg, 80.6%) as a solid. LRMS (+ESI) m/z: 409.0. ¹HNMR (400 MHz, CDCl₃) δ 7.31-7.33 (m, 2H); 7.02-7.06 (m, 2H); 4.93 (s,1H); 4.00-4.47 (m, 2H); 3.73 (s, 3H); 3.50-3.70 (m, 2H); 3.00-3.24 (m,2H); 2.37-2.39 (m, 1H); 2.05-2.10 (m, 1H).

Step 12: methyl2-(4-fluorobenzyl)-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxylate

To a solution of6-bromo-2-(4-fluorobenzyl)-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(100 mg, 0.25 mmol) in ˜1:4 DMSO/CH₃OH (5 mL) was added DIEA (129 mg,1.0 mmol) and Pd(PPh₃)₄ (23 mg, 0.02 mmol). The resulting mixture wasstirred at 80° C. for 16 h under a balloon of CO_((g)). The resultingresidue was purified by preparative thin layer chromatography(CH₂Cl₂/CH₃OH=10:1) to provide the title compound (40 mg, 42%) as awhite solid. LRMS (+ESI) m/z: 387.1.

Step 13:2-(4-fluorobenzyl)-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxylicacid

To a solution of methyl2-(4-fluorobenzyl)-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxylate(150 mg, 0.386 mmol) in CH₃OH (10 mL) was added aqueous 1 N LiOH (1.2mL). The resulting solution was stirred at room temperature for 2 h. Tothe reaction mixture was added water (10 mL) and it was then extractedwith CH₂Cl₂ (4×15 mL), and concentrated in vacuo to provide the titlecompound (120 mg, 83%), which was carried on to the subsequent stepwithout further purification. LRMS (+ESI) m/z: 373.1.

Step 14:2-(4-fluorobenzyl)-8-methoxy-N-methyl-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution of2-(4-fluorobenzyl)-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxylicacid (120 mg, 0.322 mmol) in DMF (8 mL) was added HATU (380 mg, 1.0mmol) and TEA (150 mg, 1.5 mmol). The resulting mixture was stirred atroom temperature for 16 h. EtOAc (20 mL) and water (20 mL) were added,the reaction mixture extracted with EtOAc (3×15 mL), washed with brine(2×10 mL), and the combined the organic layers dried over Na₂SO₄ andconcentrated in vacuo. The resulting residue was purified by preparativethin layer chromatography (CH₂Cl₂/CH₃OH=10:1) to provide the titlecompound (100 mg, 80%). LRMS (+ESI) m/z: 386.1.

Step 15:2-(4-fluorobenzyl)-8-hydroxy-N-methyl-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution of2-(4-fluorobenzyl)-8-methoxy-N-methyl-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide(100 mg, 0.26 mmol) in DMF (3 mL) was added anhydrous LiCl (40 mg, 1.0mmol). The resulting solution was heated to 110° C. for 2 h under N₂with stirring. The reaction mixture was purified directly by reversephase chromatography (YMC™ Actus Triart C18 150×30 mm; 27 to 57%CH₃CN/water with 0.075% TFA modifier over 8 min) to provide compound 17(33 mg, 33%) as a white solid. LRMS (+ESI) m/z: 372.1. ¹H NMR (400 MHz,MeOD) δ 7.33-7.43 (m, 2H); 7.08-7.13 (m, 2H); 4.75-4.83 (m, 3H);3.81-3.91 (m, 2H); 3.58-3.70 (m, 2H); 2.90 (s, 3H); 2.45 (s, 1H); 1.90(s, 1H).

Example 9 Preparation of Compound 18

Step 1:(5-(ethylcarbamoyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizin-3-yl)methyl methanesulfonate

N-ethyl-3-(hydroxymethyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizine-5-carboxamidewas prepared according to the route detailed in Example 8, substitutingethylamine for benzylamine.

To a solution ofN-ethyl-3-(hydroxymethyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizine-5-carboxamide(330 mg, 1.23 mmol) in CH₂Cl₂ (15 mL) was added TEA (400 mg, 4.0 mmol)and MsCl (285 mg, 2.5 mmol), and the mixture was stirred at roomtemperature for 2 h. Water (20 mL) was added and the reaction mixturewas extracted with CH₂Cl₂ (3×100 mL), and then concentrated in vacuo toprovide the title compound (300 mg, 70%), which was carried on to thesubsequent step without further purification. LRMS (+ESI) m/z: 345.1.

Step 2:2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

A mixture of Cs₂CO₃ (530 mg, 1.5 mmol) in DMF (5 mL) was stirred at 105°C. for 30 min. Next,(5-(ethylcarbamoyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizin-3-yl)methylmethanesulfonate (300 mg, 0.87 mmol) in DMF (10 mL) was added dropwise,and the mixture was stirred at the room temperature for 2 h. The mixturewas cooled to room temperature, water (50 mL) was added, the reactionmixture was extracted with CH₂Cl₂ (3×30 mL), and then concentrated invacuo. The resulting residue was purified by preparative thin layerchromatography (CH₂Cl₂/CH₃OH=10:1) to provide the title compound (130mg, 61%) as a yellow oil. LRMS (+ESI) m/z: 249.1. ¹H NMR (400 MHz,CDCl₃) δ 7.19 (s, 1H); 4.94-4.99 (m, 1H); 3.97 (s, 3H); 3.66-3.70 (m,2H); 3.63-3.65 (m, 2H); 3.37-3.39 (m, 2H); 2.63-2.69 (m, 1H); 2.11-2.17(m, 1H); 1.24-1.27 (m, 3H).

Step 3:6-bromo-2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

To a solution of2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(130 mg, 0.53 mmol) in CH₂Cl₂ (10 mL) was added NBS (179 mg, 1.0 mmol).The mixture was stirred at the room temperature for 2 h. The reactionmixture was purified directly by preparative thin layer chromatography(CH₂Cl₂/CH₃OH=10:1) to provide the title compound (160 mg, 93%) as ayellow solid. LRMS (+ESI) m/z: 328.0. ¹H NMR: (400 MHz, CDCl₃) δ4.54-4.56 (m, 1H), 4.03 (s, 3H), 3.60-3.73 (m, 4H), 3.26-3.33 (m, 2H),2.47-2.49 (m, 1H), 2.05-2.09 (m, 1H), 1.21-1.27 (m, 3H).

Step 4:N-(2,4-difluorobenzyl)-2-ethyl-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution of6-bromo-2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(160 mg, 0.48 mmol) in DMSO/CH₃OH (1 mL/4 mL) was added DIEA (205 mg,1.05 mmol), (2,4-difluorophenyl)methanamine (143 mg, 1.0 mmol), andPd(PPh₃)₄ (23 mg, 0.02 mmol). The mixture was stirred at 80° C. under anatmosphere of CO_((g)) (balloon) for 16 h. The reaction mixture waspurified directly by preparative thin layer chromatography(CH₂Cl₂/CH₃OH=10:1) to provide the title compound (50 mg, 24.5%) as ayellow solid. LRMS (+ESI) m/z: 418.2.

Step 5:N-(2,4-difluorobenzyl)-2-ethyl-8-hydroxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution ofN-(2,4-difluorobenzyl)-2-ethyl-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide(50 mg, 0.117 mmol) in DMF (3 mL) was added anhydrous LiCl (20 mg, 0.5mmol). The resulting solution was heated at 110° C. for 2 h under N₂with stirring. The reaction mixture was purified directly by reversephase chromatography (YMC™ Actus Triart C18 150×30 mm; 31 to 61%CH₃CN/water with 0.075% TFA modifier over 8 min) to provide compound 18(27 mg, 56.5%) as a white solid. MS (+ESI) m/z: 404.1. ¹H NMR (400 MHz,DMSO-d₆) δ 11.30 (s, 1H); 10.89 (s, 1H); 7.36-7.37 (m, 1H); 7.19-7.22(m, 1H); 7.04-7.06 (m, 1H); 4.54-4.65 (m, 3H); 3.74-3.84 (m, 4H);2.54-2.56 (m, 3H); 1.82-1.84 (m, 1H); 1.10-1.14 (m, 3H).

Example 10 Preparation of Compound 24

Step 1:2-ethyl-5-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

To a stirred solution of2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(Example 9, 150 mg, 0.60 mmol) in dry THF (30 mL) cooled to −78° C.under N₂ was added a 1 N THF solution of LiHMDS (1.8 mL, 1.8 mmol).After 1 h, Davis oxaziridine (224 mg, 1.0 mmol) in THF (100 mL) wasslowly added, the mixture warmed slowly to room temperature, and thenstirred for 1 h. The reaction was quenched with saturated aqueous NH₄Cl(10 mL), and the mixture was extracted with EtOAc (3×20 mL). Thecombined extracts were washed with water (2×20 mL) and brine (3×20 mL),concentrated in vacuo, and the resulting residue was purified bypreparative thin layer chromatography (CH₂Cl₂/CH₃OH=8:1) to provide thetitle compound (70 mg, 46%) as a mixture of diastereomers. MS (+ESI)m/z: 265.1. ¹H NMR: (400 MHz, CH₃OD) δ 6.64 (s, 1H); 5.17-5.18 (m, 1H);3.90 (s, 3H); 3.82-3.85 (m, 1H); 3.65-3.70 (m, 4H); 2.41-2.45 (m, 1H);2.20-2.21 (m, 1H); 1.25-1.27 (m, 3H).

Step 2:6-bromo-2-ethyl-5-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

To a solution of2-ethyl-5-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(70 mg, 0.27 mmol) in CH₂Cl₂ (10 mL) was added anhydrous NBS (179 mg,1.0 mmol). The mixture was stirred at room temperature for 2 h. Themixture was concentrated in vacuo and then purified directly bypreparative thin layer chromatography (CH₂Cl₂/CH₃OH=10:1) to provide thetitle compound (75 mg, 83%) as a yellow solid. MS (+ESI) m/z: 344.0. ¹HNMR (400 MHz, CH₃OD) δ 5.37-5.42 (m, 1H); 4.97-5.00 (m, 1H); 3.92 (s,3H); 3.62-3.73 (m, 4H); 2.62-2.46 (m, 1H); 2.19-2.27 (m, 1H); 1.23-1.27(m, 3H).

Step 3:N-(2,4-difluorobenzyl)-2-ethyl-5-hydroxy-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution of6-bromo-2-ethyl-5-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(75 mg, 0.22 mmol) in DMSO/CH₃OH (1.5/6 mL) was added DIEA (205 mg, 1.00mmol), (2,4-difluorophenyl)methanamine (143 mg, 1.0 mmol) and Pd(PPh₃)₄(23 mg, 0.02 mmol). The mixture was stirred at 80° C. under anatmosphere of CO_((g)) (balloon) for 16 h. The mixture was concentratedin vacuo, and then purified directly by preparative thin layerchromatography (CH₂Cl₂/CH₃OH=8:1) to provide the title compound (40 mg,51%) as a pale yellow solid. MS (+ESI) m/z: 434.1.

Step 4:N-(2,4-difluorobenzyl)-2-ethyl-5,8-dihydroxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution ofN-(2,4-difluorobenzyl)-2-ethyl-5-hydroxy-8-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide(45 mg, 0.103 mmol) in DMF (3 mL) was added anhydrous LiCl (20 mg, 0.5mmol). The resulting solution was heated at 110° C. for 2 h under N₂with stirring. The reaction mixture was purified directly by reversephase chromatography (Synergi™ Max-RP C18 4 um 30×150 mm column; 25 to55% CH₃CN/water with 0.075% TFA modifier over 8 minutes) to providecompound 24 (9.5 mg, 21.3%) as a white solid. MS (+ESI) m/z: 420.1. ¹HNMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H); 10.86 (s, 1H); 7.41-7.44 (m,1H); 7.25-7.27 (m, 1H); 7.08-7.09 (m, 1H); 5.78-5.79 (m, 1H); 4.53-4.57(m, 3H); 3.62-3.63 (m, 5H); 2.23-2.28 (m, 1H); 2.10-2.13 (m, 1H);1.12-1.16 (m, 3H).

Example 11 Preparation of Compound 26

Step 1:2-Ethyl-3-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

A solution of oxalyl chloride (0.49 mL, 5.63 mmol) in CH₂Cl₂ (6 mL) wascooled to −78° C. and a solution of DMSO (0.53 mL, 7.51 mmol) in CH₂Cl₂(6 mL) was added dropwise to the stirring mixture. After 20 minutes, asolution ofN-ethyl-3-(hydroxymethyl)-6-methoxy-7-oxo-1,2,3,7-tetrahydroindolizine-5-carboxamide(500 mg, 1.88 mmol) in CH₂Cl₂ (6 mL) was added dropwise to the reactionmixture at the same temperature. The mixture was stirred at −78° C. for1 h. DIEA (1.64 mL, 9.39 mmol) was then added to the mixture and theresulting mixture was allowed to warm to room temperature overnight. Thereaction mixture was concentrated in vacuo to provide the titlecompound, which was carried on to the subsequent step without furtherpurification. Assume quantitative yield. MS (+ESI) m/z: 265.2.

Step 2:(cis)-2-ethyl-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(trans)-2-ethyl-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

To the unpurified mixture of2-ethyl-3-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(496 mg, 1.88 mmol) in DMF (19 mL) was added 60% NaH (375 mg, 9.4 mmol)followed by CH₃I (0.35 mL, 5.6 mmol) and the mixture stirred at roomtemperature. After 10 minutes, an additional 5 equivalents of 60% NaH(375 mg, 9.4 mmol) and an additional 4 equiv. of CH₃I (0.47 mL, 7.5mmol) were added and the mixture stirred for 10 min at room temperature.The mixture was cooled to 0° C. and quenched by dropwise addition ofMeOH (5 mL). The reaction mixture was then concentrated to dryness byazeotroping with toluene. The resulting residue was purified by gradientelution on reverse phase (50×250 mm (10 um) Phenomenex Prep C18; 0 to50% CH₃CN/water w/ 0.1% TFA modifier over 30 min at 90 mL/min) toseparate diastereomers and afford(cis)-2-ethyl-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(224 mg, 42%) (first eluting diastereomer) as a tan gum and(trans)-2-ethyl-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(59 mg, 11%) as a tan gum. MS (+ESI) m/z: 279.3.

Step 3:(cis)-2-ethyl-6-iodo-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

To a solution of(Cis)-2-ethyl-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(280 mg, 1.0 mmol) in CH₂Cl₂ (10 mL) was added NIS (453 mg, 2.0 mmol).The mixture was stirred at the room temperature for 15 min. The reactionmixture was filtered washing with minimal CH₂Cl₂ and concentrated todryness to afford the title compound as a dark brown solid, which wascarried on to the subsequent step without further purification. Assumequantitative yield. MS (+ESI) m/z: 405.2.

Step 4:(3R,3aS)-N-(3-chloro-4-fluorobenzyl)-2-ethyl-3,8-dimethoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution of unpurified racemic(cis)-2-ethyl-6-iodo-3,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(407 mg, 1.0 mmol) in DMSO (20 mL) was added DIEA (0.86 mL, 5.0 mmol),(3-chloro-4-fluorophenyl)methanamine (632 mg, 4.0 mmol), and Pd(PPh₃)₄(172 mg, 0.15 mmol). The reaction vessel was evacuated and backfilled 3×with CO_((g)). The mixture was stirred at 100° C. under an atmosphere ofCO_((g)) (balloon) for 2 h. The mixture was partitioned between water(30 mL) and EtOAc (200 mL). The organic phase was washed with water(4×30 mL) and brine (50 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting residue was purified by gradientelution on reverse phase (50×250 mm (10 um) Phenomenex Prep C18; 20 to70% CH₃CN/water w/ 0.1% TFA modifier over 30 min at 90 mL/min) andrepurified by gradient elution on silica gel (RediSep-Gold-12 g, 20 to100% EtOAc in hexanes and the 100% [10% MeOH in EtOAc], 35 minutegradient) to separate the product from triphenylphosphine oxide andprovide the title compound (190 mg, 41%) as yellow foam. MS (+ESI) m/z:464.3. 1H NMR (500 MHz, CDCl3): δ 10.99 (s, 1H); 7.39 (d, J=7.0 Hz, 1H);7.21 (s, 1H); 7.07 (t, J=8.7 Hz, 1H); 4.73 (s, 1H); 4.60 (dd, J=15.2,6.2 Hz, 1H); 4.45-4.49 (m, 2H); 4.27 (dq, J=13.7, 7.2 Hz, 1H); 4.12 (dd,J=18.9, 8.7 Hz, 1H); 4.05 (s, 3H); 3.42 (s, 3H); 3.23 (dq, J=13.7, 7.2Hz, 1H); 2.30-2.37 (m, 2H); 1.31 (t, J=7.1 Hz, 3H).

Enantiomers were separated by chiral preparative SFC (2-cm×25-cm OJ-Hcolumn; isocratic [15% (0.1% DEA/CH3OH)]/[85% CO2]; 50 mL/min flowrate;254 nm; dissolved in MeOH; 1 mL/injection) to provide(3R,3aS)-N-(3-chloro-4-fluorobenzyl)-2-ethyl-3,8-dimethoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamideand(3R,3aR)-N-(3-chloro-4-fluorobenzyl)-2-ethyl-3,8-dimethoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamideas off-white solids. The first eluting enantiomer was determined to bethe compound of interest.

Step 6:(3R,3aS)-N-(3-chloro-4-fluorobenzyl)-2-ethyl-8-hydroxy-3-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

To a solution of(3R,3aS)-N-(3-chloro-4-fluorobenzyl)-2-ethyl-3,8-dimethoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide(156 mg, 0.34 mmol) in DMF (6.7 mL) was added anhydrous LiCl (428 mg,10.1 mmol). The resulting solution was heated at 100° C. for 2 h underN₂ with stirring. The reaction mixture was purified directly by gradientelution on reverse phase (30×150 mm (5 μm) SunFire Prep C18; 20 to 70%CH₃CN/water w/ 0.1% TFA modifier over 20 min at 40 mL/min) to providecompound 26 (115 mg, 76%) as a peach foam. MS (+ESI) m/z: 450.3. 1H NMR(500 MHz, CDCl3): δ 10.92 (s, 1H); 7.38 (d, J=6.9 Hz, 1H); 7.21 (s, 1H);7.07 (t, J=8.7 Hz, 1H); 5.30 (s, 1H); 4.83 (s, 1H); 4.58 (dd, J=15.5,5.7 Hz, 1H); 4.52 (t, J=9.7 Hz, 1H); 4.26 (dd, J=13.9, 7.2 Hz, 1H); 4.11(dd, J=18.9, 9.0 Hz, 1H); 3.48 (s, 3H); 3.35-3.43 (m, 1H); 3.27-3.31 (m,1H); 2.01 (s, 2H); 1.33 (t, J=7.1 Hz, 3H).

Example 12 Preparation of Compound 30

Step 1:2-ethyl-5-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

A solution2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(1.2 g, 4.83 mmol) in THF (40 mL) was cooled to −78° C. and treateddropwise with LiHMDS (1M in tetrahydrofuran, 9.67 ml, 9.67 mmol) andstirred at −78° C. for 1 h (light orange solution turns deep purple).The mixture was treated with a solution of3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (Davis oxaziridine) (1.516g, 5.80 mmol) in THF (8 mL) and then removed from the dry ice bath andstirred for 10 min as it warmed to room temperature. The reactionmixture was concentrated and the residue was dissolved in MeOH andpurified directly by gradient elution on reverse phase (50×250 mm (5 μm)Sunfire Prep C18; 0 to 50% CH₃CN/water w/ 0.1% TFA modifier over 30 minat 90 mL/min, 2 injections) to yield the title compound (467 mg, 37%) asa tan film. LRMS (+ESI) m/z=265.2.

Step 2:2-ethyl-5,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

A solution of2-ethyl-5-hydroxy-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(467 mg, 1.767 mmol) in DMF (8.8 mL) was treated with NaH (212 mg, 5.30mmol) and CH₃I (221 μl, 3.53 mmol) at room temperature and stirred for10 min. The mixture was then quenched with a 5 drops of water andconcentrated to dryness, azeotroping with toluene (3×). The residue wasdissolved in water/CH₃OH, filtered through a syringe filter, andpurified directly by gradient elution on reverse phase (50×250 mm (5 μm)Sunfire Prep C18; 5 to 95% CH₃CN/water w/ 0.1% TFA modifier over 30 minat 90 mL/min, 1 injection). Pure fractions were concentrated in vacuo toyield the title compound (247 mg, 50%) as a tan film. LRMS (+ESI)m/z=279.2.

Step 3:2-ethyl-6-iodo-5,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

A solution of2-ethyl-5,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(247 mg, 0.888 mmol) in CH₂Cl₂ (22.8 mL) was treated withN-iodosuccinimide (399 mg, 1.775 mmol) and stirred at room temperaturefor 20 min. The mixture was treated with additional N-iodosuccinimide(399 mg, 1.775 mmol) four times over 1 h. The reaction mixture wasfiltered through a fine fritted scintered glass funnel and the filtratewas concentrated. The isolated material was used in the subsequent stepwithout further purification assuming quantitative conversion. Theoverall yield was not determined. LRMS (+ESI) m/z=405.2.

Step 4:(3aS,5R)-N-(2,4-difluorobenzyl)-2-ethyl-5,8-dimethoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

A suspension of2-ethyl-6-iodo-5,8-dimethoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(359 mg, 0.888 mmol), Pd(PPh₃)₄ (103 mg, 0.089 mmol),2,4-difluorophenyl)methanamine (509 mg, 3.55 mmol), and DIEA (776 μl,4.44 mmol) in DMSO (8.8 mL) was degassed with a stream of N_(2 (g)).Next, the flask was evacuated and back-filled with CO_((g)) and stirredunder a CO_((g)) atmosphere (1 atm) at 100° C. for 25 min. The mixturewas partitioned between water (50 mL) and EtOAc (50 mL). The organicphase was washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The resulting residue wasfirst purified by gradient elution on silica gel (RediSep-Rf-40 g, 0 to100% 10% CH₃OH in CH₂Cl₂/CH₂Cl₂, 20 minute gradient) to afford ˜300 mgof impure material. This impure material was purified again by gradientelution on silica gel (RediSep-Rf-24 g, 0 to 100% 10% CH₃OH inEtOAc/hexanes, 20 minute gradient) to afford the pure trans diastereomerof the title compound (84 mg, 21%) as a tan foam. LRMS (+ESI) m/z=448.3.The cis diastereomer is also isolated cleanly in this purification.

Enantiomers were separated by chiral preparative SFC (2-cm×25-cm AD-Hcolumn; isocratic [40% (0.1% DEA/CH₃OH)]/[60% CO₂]; 70 mL/min flowrate;254 nm) to provide enantiopure title compounds as tan foams. The firsteluting enantiomer was determined to be the enantiomer of interest.

Step 5:(3aS,5R)-N-(2,4-difluorobenzyl)-2-ethyl-8-hydroxy-5-methoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide

A solution of(3aS,5R)-N-(2,4-difluorobenzyl)-2-ethyl-5,8-dimethoxy-1,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-6-carboxamide(61 mg, 0.136 mmol) in DMF (1363 μl) was treated with LiCl (173 mg, 4.09mmol) and stirred at 100° C. for 30 min. The mixture was diluted withMeOH, filtered and purified directly by gradient elution on reversephase (30×150 mm (5 μm) Sunfire Prep C18; 5 to 95% CH₃CN/water w/ 0.1%TFA modifier over 20 min @ 40 mL/min, 1 injection), to yield Compound 30(45 mg, 76%) as a pale orange foam. LRMS (+ESI) m/z=434.3. ¹H NMR (500MHz, CDCl₃): δ 10.83 (s; 1H); 7.38 (d; J=8.14 Hz; 1H); 6.80-6.83 (m;2H); 5.97 (d; J=4.56 Hz; 1H); 4.69 (d; J=13.11 Hz; 2H); 4.61 (d; J=15.61Hz; 1H); 3.66-3.69 (m; 4H); 3.47 (s; 3H); 2.54 (dd; J=12.87; 4.92 Hz;1H); 1.98 (m; 1H); 1.27 (t; J=6.99 Hz; 3H).

Example 13 Preparation of Compound 35

Step 1:6-bromo-2-ethyl-8-methoxy-5-methyl-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione

A stirred solution of6-bromo-2-ethyl-8-methoxy-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(Example 9, 50 mg, 0.153 mmol) in dry THF (30 mL) was cooled to −78° C.under N₂. To the resulting solution was added a solution of LiHMDS (0.48mL, 1N in THF, 0.48 mmol). After 1 h, the CH₃I (80 mg, 0.5 mmol) in THF(10 mL) was added at −78° C., and the mixture was stirred for 1 h atroom temperature. The reaction was quenched with saturated NH₄Cl (10mL), and the mixture was extracted with EtOAc (20 mL×3). The combinedextracts were washed with water and brine, and evaporated. The resultingresidue was purified by preparative thin layer chromatography(CH₂Cl₂/CH₃OH=10:1) to afford the title compound (30 mg, 57%) as ayellow solid in a 10:1 mixture of diastereomers. LRMS (+ESI) m/z=342. ¹HNMR (400 MHz, CDCl₃): δ 6.64 (s, 1H), 4.63-4.66 (m, 1H), 4.04-4.05 (m,1H), 3.53-3.62 (m, 6H), 2.12-2.16 (m, 2H), 1.38-1.40 (m, 3H), 1.12-1.24(m, 3H).

Step 2:N-(2,4-difluorobenzyl)-2-ethyl-9-methoxy-6-methyl-1,8-dioxo-2,3,3a,5,6,8-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-7-carboxamide

To a solution of6-bromo-2-ethyl-8-methoxy-5-methyl-3,3a,4,5-tetrahydro-1H-pyrazino[2,1,6-cd]indolizine-1,7(2H)-dione(30 mg, 0.085 mmol) in 1:3 DMSO/CH₃OH (5 mL) was added DIEA (170 mg, 0.8mmol), (4-fluoro-2-methoxyphenyl)methanamine (80 mg, 0.6 mmol), andPd(PPh₃)₄ (10 mg, 0.016 mmol). The mixture was stirred at 80° C.overnight under CO_((g)) balloon. The reaction mixture was purifieddirectly by preparative thin layer chromatography (CH₂Cl₂/CH₃OH=10:1) toafford the title compound (5 mg, 14.2%) as a white solid as a mixturediastereomers.

Enantiomers were separated by chiral preparative SFC (4.6 mm×150 mmChiralpak AS-H column; gradient [5 to 40% (0.05% DEA/CH₃OH)]/[CO₂]; 3mL/min flowrate; 220 nm) to provide each enantiomer of the majordiastereomer. The first eluting enantiomer was determined to be theenantiomer of interest. LRMS (+ESI) m/z=432. ¹H NMR (400 MHz, CDCl₃): δ11.02 (s, 1H), 7.29-7.32 (m, 1H), 6.69-6.76 (m, 2H), 4.54-4.56 (m, 3H),3.96 (s, 3H), 3.59-3.77 (m, 4H), 2.01-2.11 (m, 3H), 1.34 (d, J=6.8 Hz,3H), 1.15 (t, J=7.2 Hz, 3H).

Step 3:N-(2,4-difluorobenzyl)-2-ethyl-9-hydroxy-6-methyl-1,8-dioxo-2,3,3a,5,6,8-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-7-carboxamide

To a solution of compoundN-(2,4-difluorobenzyl)-2-ethyl-9-methoxy-6-methyl-1,8-dioxo-2,3,3a,5,6,8-hexahydro-1H-pyrazino[2,1,6-cd]indolizine-7-carboxamide(15 mg, 0.033 mmol) in DMF (3 mL) was added anh. LiCl (20 mg, 0.5 mmol).The resulting solution was heated to 110° C. for 2 h under N₂ withstirring. The product was purified by prep-HPLC (Agela DuraShell C18150*25*5 μm using water and acetonitrile as the eluents. Mobile phase A:water (containing 0.05% TFA), mobile phase B: acetonitrile. Gradient:30% to 60% B, 0-8.0 min. Flow Rate: 35 mL/min) to afford the titlecompound (9.04 mg, 64.6%) as a white solid. LRMS (+ESI) m/z=418. ¹H NMR(400 MHz, CDCl₃): δ 10.29 (s, 1H), 7.26-7.32 (m, 1H), 6.70-7.78 (m, 2H),4.53-4.58 (m, 3H), 3.51-3.63 (m, 4H), 2.09-2.13 (m, 3H), 1.33-1.35 (m,3H), 1.17-1.30 (m, 3H).

Example 14 Preparation of Compound 34

Step A: Synthesis of Intermediate Compound 14b

Step A was performed using the method described above in Example 12,Step 1 and using the indicated starting material and reagents to providecompound 14b. LRMS ESI [M+1]⁺=265.2

Step B: Synthesis of Intermediate Compound 14c

Step B was performed using the method described above in Example 12,Step 2 and using the indicated starting material and reagents to providecompound 14c. LRMS ESI [M+1]⁺=279.2

Step C: Synthesis of Intermediate Compound 14d

Step C was performed using the method described above in Example 12,Step 3 and using the indicated starting material and reagents to providecompound 14d. LRMS ESI [M+1]⁺=405.2

Step D: Synthesis of Intermediate Compound 14e

Step D was performed using the method described above in Example 12,Step 4 and using the indicated starting material and reagents to providecompound 14e. LRMS ESI [M+1]⁺=482.2

Step E: Synthesis of Intermediate Compounds 14f and 14g

Step E (separation of the enantiomers of compound 14e) was performedusing the chiral separation method described above in Example 12, Step 4to provide compounds 14f and 14g. LRMS ESI [M+1]⁺=482.2 (for both 14fand 14g).

Step F: Synthesis of Compound 34

Step F was performed using the method described above in Example 12,Step 5 and using the indicated starting material and reagents to providecompound 34. LRMS ESI [M+1]⁺=468.2. ¹H NMR (ppm)(CDCl₃): δ 10.78 (1H,s), 7.32 (1H, q, J=7.37 Hz), 6.93 (1H, t, J=8.44 Hz), 5.85 (1H, d,J=5.00 Hz), 4.59-4.70 (3H, m), 3.77 (1H, t, J=12.24 Hz), 3.54-3.70 (3H,m), 3.45 (3H, s), 2.49 (1H, dd, J=13.03, 5.15 Hz), 1.97-2.02 (1H, m),1.26 (3H, t, J=7.15 Hz).

The following comprehensive list of illustrative compounds of thepresent invention, listed in Table A below, were made using the methodsdescribed in the Examples above.

TABLE A Com- Preparative LRMS pound Method (ESI) No. Structure Used [M +1]⁺ 1

  racemic Example 4 406 2

  racemic Example 4 434 3

  single enantiomer Example 4 434 4

  racemic Example 4 448 5

  racemic Example 4 450 6

  mixture of stereoisomers Example 4 478 7

  racemic Example 4 483 8

  racemic Example 4 512 9

  single enantiomer Example 4 452 10

  racemic Example 4 450 11

  racemic Example 4 448 12

  racemic Example 4 468 13

  single enantiomer Example 5 475 14

  racemic Example 6 457 15

  single enantiomer Example 6 457 16

  racemic Example 7 461 17

  racemic Example 8 372 18

  racemic Example 9 404 19

  racemic Example 9 464 20

  single enantiomer Example 9 472 21

  single enantiomer Example 9 448 22

  single enantiomer Example 9 448 23

  single enantiomer Example 9 466 24

  racemic Example 10 420 25

  racemic Example 11 434 26

  single enantiomer Example 11 450 27

  single enantiomer Example 11 464 28

  single enantiomer Example 11 448 29

  racemic Example 12 434 30

  single enantiomer Example 12 434 31

  single enantiomer Example 12 434 32

  single enantiomer Example 12 464 33

  single enantiomer Example 12 460 34

  single enantiomer Example 12 468 35

  single enantiomer Example 13 418 36

  single enantiomer Example 13 448 37

  single enantiomer Example 13 436 38

  single enantiomer Example 12 448

Example 15 Assessing Antiviral Potency in a Multiple Round HIV-1Infection Assay

HIV-1 replication was monitored using MT4-gag-GFP clone D3 (hereafterdesignate MT4-GFP), which are MT-4 cells modified to harbor a GFPreporter gene, the expression of which is dependent on the HIV-1expressed proteins tat and rev. Productive infection of an MT4-GFP cellwith HIV-1 results in GFP expression approximately 24 h post-infection.

MT4-GFP cells were maintained at 37° C./5% CO₂/90% relative humidity inRPMI 1640 supplemented with 10% fetal bovine serum, 100 U/mlpenicillin/streptomycin, and 400 μg/ml G418 to maintain the reportergene. For infections, MT4-GFP cells were placed in the same mediumlacking G418 and infected overnight with HIV-1 (NL4-3 strain) virus atan approximate multiplicity of infection of 0.01 in the same incubationconditions.

Cells were then washed and resuspended in either RPMI 1640 supplementedwith 10% normal human serum (NHS) or without NHS at 1.6×10⁵ cells/mL(10% NHS or serum-free conditions) or in 100% normal human serum at2×10⁵ cells/mL (100% NHS conditions). Compound plates were prepared bydispensing compounds dissolved in DMSO into wells of 384 well poly Dlysine-coated plates (0.2 μl/well) using an ECHO acoustic dispenser.Each compound was tested in a 10 point serial 3-fold dilution (typicalfinal concentrations: 8.4 μM-0.42 nM). Controls included no inhibitor(DMSO only) and a combination of three antiviral agents (efavirenz,indinavir, and the integrase strand transfer inhibitor L-002254051 atfinal concentrations of 4 μM each). Cells were added (50 μL/well) tocompound plates and the infected cells were maintained at 37° C./5%CO₂/90% relative humidity. Results for selected compounds of the presentinvention are shown below in Table B.

TABLE B Compound No. Wild Type Cell Assay IP % NHS 1 9.2 nM 0 2 33 nM 103 13 nM 0 4 21 nM 10 5 9.2 nM 0 6 24 nM 0 7 9.6 nM 0 8 23 nM 0 9 20 nM10 10 100 nM 10 11 116 nM 10 12 50 nM 10 13 5 nM 0 14 323 nM 0 15 234 nM0 16 17 nM 0 17 35 nM 0 18 2.6 nM 0 19 4.4 nM 0 20 3.8 nM 0 21 3.1 nM 022 2.8 nM 0 23 3.8 nM 0 24 2.2 nM 0 25 1.9 nM 0 26 3.2 nM 0 27 2.3 nM 028 2.1 nM 0 29 1.2 nM 0 30 1.0 nM 0 31 3.8 nM 0 32 2.3 nM 0 33 2.3 nM 034 2.9 nM 0 35 1.2 nM 0 36 3.9 nM 0 37 1.1 nM 0 38 1.9 nM 0

Uses of the Fused Tricyclic Heterocycle Derivatives

The Fused Tricyclic Heterocycle Derivatives are useful in human andveterinary medicine for treating or preventing HIV infection in asubject. In one embodiment, the Fused Tricyclic Heterocycle Derivativescan be inhibitors of HIV viral replication. In a specific embodiment,the Fused Tricyclic Heterocycle Derivatives are inhibitors of HIV-1.Accordingly, the Fused Tricyclic Heterocycle Derivatives are useful fortreating HIV infections and AIDS. In accordance with the invention, theFused Tricyclic Heterocycle Derivatives can be administered to a subjectin need of treatment or prevention of HIV infection.

Accordingly, in one embodiment, the invention provides methods fortreating HIV infection in a subject comprising administering to thesubject an effective amount of at least one Fused Tricyclic HeterocycleDerivative or a pharmaceutically acceptable salt thereof. In a specificembodiment, the present invention provides methods for treating AIDS ina subject comprising administering to the subject an effective amount ofat least one Fused Tricyclic Heterocycle Derivative or apharmaceutically acceptable salt thereof.

Treatment or Prevention of HIV Infection

The Fused Tricyclic Heterocycle Derivatives are useful in the inhibitionof HIV, the treatment of HIV infection and/or reduction of thelikelihood or severity of symptoms of HIV infection and the inhibitionof HIV viral replication and/or HIV viral production in a cell-basedsystem. For example, the Fused Tricyclic Heterocycle Derivatives areuseful in treating infection by HIV after suspected past exposure to HIVby such means as blood transfusion, exchange of body fluids, bites,accidental needle stick, or exposure to subject blood during surgery orother medical procedures.

In one embodiment, the HIV infection has progressed to AIDS.

Accordingly, in one embodiment, the invention provides methods fortreating HIV infection in a subject, the methods comprisingadministering to the subject an effective amount of at least one FusedTricyclic Heterocycle Derivative or a pharmaceutically acceptable saltthereof. In a specific embodiment, the amount administered is effectiveto treat or prevent infection by HIV in the subject. In another specificembodiment, the amount administered is effective to inhibit HIV viralreplication and/or viral production in the subject.

The Fused Tricyclic Heterocycle Derivatives are also useful in thepreparation and execution of screening assays for antiviral compounds.For example the Fused Tricyclic Heterocycle Derivatives are useful foridentifying resistant HIV cell lines harboring mutations, which areexcellent screening tools for more powerful antiviral compounds.Furthermore, the Fused Tricyclic Heterocycle Derivatives are useful inestablishing or determining the binding site of other antivirals to theHIV Integrase.

The compositions and combinations of the present invention can be usefulfor treating a subject suffering from infection related to any HIVgenotype.

Combination Therapy

In another embodiment, the present methods for treating or preventingHIV infection can further comprise the administration of one or moreadditional therapeutic agents which are not Fused Tricyclic HeterocycleDerivatives.

In one embodiment, the additional therapeutic agent is an antiviralagent.

In another embodiment, the additional therapeutic agent is animmunomodulatory agent, such as an immunosuppressive agent.

Accordingly, in one embodiment, the present invention provides methodsfor treating a viral infection in a subject, the method comprisingadministering to the subject: (i) at least one Fused TricyclicHeterocycle Derivative (which may include two or more different FusedTricyclic Heterocycle Derivatives), or a pharmaceutically acceptablesalt thereof, and (ii) at least one additional therapeutic agent that isother than a Fused Tricyclic Heterocycle Derivative, wherein the amountsadministered are together effective to treat or prevent a viralinfection.

When administering a combination therapy of the invention to a subject,therapeutic agents in the combination, or a pharmaceutical compositionor compositions comprising therapeutic agents, may be administered inany order such as, for example, sequentially, concurrently, together,simultaneously and the like. The amounts of the various actives in suchcombination therapy may be different amounts (different dosage amounts)or same amounts (same dosage amounts). Thus, for non-limitingillustration purposes, a Fused Tricyclic Heterocycle Derivative and anadditional therapeutic agent may be present in fixed amounts (dosageamounts) in a single dosage unit (e.g., a capsule, a tablet and thelike).

In one embodiment, the at least one Fused Tricyclic HeterocycleDerivative is administered during a time when the additional therapeuticagent(s) exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the at least one Fused Tricyclic HeterocycleDerivative and the additional therapeutic agent(s) are administered indoses commonly employed when such agents are used as monotherapy fortreating a viral infection.

In another embodiment, the at least one Fused Tricyclic HeterocycleDerivative and the additional therapeutic agent(s) are administered indoses lower than the doses commonly employed when such agents are usedas monotherapy for treating a viral infection.

In still another embodiment, the at least one Fused TricyclicHeterocycle Derivative and the additional therapeutic agent(s) actsynergistically and are administered in doses lower than the dosescommonly employed when such agents are used as monotherapy for treatinga viral infection.

In one embodiment, the at least one Fused Tricyclic HeterocycleDerivative and the additional therapeutic agent(s) are present in thesame composition. In one embodiment, this composition is suitable fororal administration. In another embodiment, this composition is suitablefor intravenous administration. In another embodiment, this compositionis suitable for subcutaneous administration. In still anotherembodiment, this composition is suitable for parenteral administration.

Viral infections and virus-related disorders that can be treated orprevented using the combination therapy methods of the present inventioninclude, but are not limited to, those listed above.

In one embodiment, the viral infection is HIV infection.

In another embodiment, the viral infection is AIDS.

The at least one Fused Tricyclic Heterocycle Derivative and theadditional therapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of therapy without reducing theefficacy of therapy.

In one embodiment, the administration of at least one Fused TricyclicHeterocycle Derivative and the additional therapeutic agent(s) mayinhibit the resistance of a viral infection to these agents.

As noted above, the present invention is also directed to use of acompound of Formula I with one or more anti-HIV agents. An “anti-HIVagent” is any agent which is directly or indirectly effective in theinhibition of HIV reverse transcriptase or another enzyme required forHIV replication or infection, the treatment or prophylaxis of HIVinfection, and/or the treatment, prophylaxis or delay in the onset orprogression of AIDS. It is understood that an anti-HIV agent iseffective in treating, preventing, or delaying the onset or progressionof HIV infection or AIDS and/or diseases or conditions arising therefromor associated therewith. For example, the compounds of this inventionmay be effectively administered, whether at periods of pre-exposureand/or post-exposure, in combination with effective amounts of one ormore anti-HIV agents selected from HIV antiviral agents,imunomodulators, antiinfectives, or vaccines useful for treating HIVinfection or AIDS. Suitable HIV antivirals for use in combination withthe compounds of the present invention include, for example, thoselisted in Table A as follows:

TABLE A Name Type abacavir, ABC, Ziagen ® nRTI abacavir + lamivudine,Epzicom ® nRTI abacavir + lamivudine + zidovudine, Trizivir ® nRTIamprenavir, Agenerase ® PI atazanavir, Reyataz ® PI AZT, zidovudine,azidothymidine, Retrovir ® nRTI CMX-157 nRTI darunavir, Prezista ® PIddC, zalcitabine, dideoxycytidine, Hivid ® nRTI ddI, didanosine,dideoxyinosine, Videx ® nRTI ddI (enteric coated), Videx EC ® nRTIdelavirdine, DLV, Rescriptor ® nnRTI Dolutegravir PI efavirenz, EFV,Sustiva ®, Stocrin ® nnRTI efavirenz + emtricitabine + tenofovir DF,Atripla ® nnRTI + nRTI Elvitegravir InI emtricitabine, FTC, Emtriva ®nRTI emtricitabine + tenofovir DF, Truvada ® nRTI emvirine, Coactinon ®nnRTI enfuvirtide, Fuzeon ® FI enteric coated didanosine, Videx EC ®nRTI etravirine, TMC-125 nnRTI fosamprenavir calcium, Lexiva ® PIindinavir, Crixivan ® PI lamivudine, 3TC, Epivir ® nRTI lamivudine +zidovudine, Combivir ® nRTI lopinavir PI lopinavir + ritonavir,Kaletra ® PI maraviroc, Selzentry ® EI nelfinavir, Viracept ® PInevirapine, NVP, Viramune ® nnRTI raltegravir, MK-0518, Isentress ® InIrilpivirine, TMC-278 nnRTI Rilpivirine + emtricitabine + tenofovir,Complera nnRTI + nRTI ritonavir, Norvir ® PI saquinavir, Invirase ®,Fortovase ® PI stavudine, d4T, didehydrodeoxythymidine, Zerit ® nRTItenofovir DF (DF = disoproxil fumarate), TDF, nRTI Viread ® tipranavir,Aptivus ® PI EI = entry inhibitor; FI = fusion inhibitor; InI =integrase inhibitor; PI = protease inhibitor; nRTI = nucleoside reversetranscriptase inhibitor; nnRTI = non-nucleoside reverse transcriptaseinhibitor. Some of the drugs listed in the table are used in a saltform; e.g., abacavir sulfate, indinavir sulfate, atazanavir sulfate,nelfinavir mesylate.

In one embodiment, the one or more anti-HIV drugs are selected fromraltegravir, lamivudine, abacavir, ritonavir, dolutegravir, darunavir,atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine andlopinavir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is raltegravir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is lamivudine.

In still another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is atazanavir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is darunavir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is rilpivirine.

In yet another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is dolutegravir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is elvitegravir.

In one embodiment, the compound of formula (I) is used in combinationwith two anti-HIV drugs which are lamivudine and abacavir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are darunavir and raltegravir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are emtricitabine andtenofovir.

In still another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are atazanavir andraltegravir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are ritonavir and lopinavir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are lamivudine andraltegravir.

In one embodiment, the compound of formula (I) is used in combinationwith three anti-HIV drug which are abacavir, lamivudine and raltegravir.

In another embodiment, the compound of formula (I) is used incombination with three anti-HIV drug which are lopinavir, ritonavir andraltegravir.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising (i) a compound of formula (I) or apharmaceutically acceptable salt thereof; (ii) a pharmaceuticallyacceptable carrier; and (iii) one or more additional anti-HIV agentsselected from lamivudine, abacavir, ritonavir and lopinavir, or apharmaceutically acceptable salt thereof, wherein the amounts present ofcomponents (i) and (iii) are together effective for the treatment orprophylaxis of infection by HIV or for the treatment, prophylaxis, ordelay in the onset or progression of AIDS in the subject in needthereof.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of infection by HIV or for the treatment,prophylaxis, or delay in the onset or progression of AIDS in a subjectin need thereof, which comprises administering to the subject (i) acompound of formula (I) or a pharmaceutically acceptable salt thereofand (ii) one or more additional anti-HIV agents selected fromlamivudine, abacavir, ritonavir and lopinavir, or a pharmaceuticallyacceptable salt thereof, wherein the amounts administered of components(i) and (ii) are together effective for the treatment or prophylaxis ofinfection by HIV or for the treatment, prophylaxis, or delay in theonset or progression of AIDS in the subject in need thereof.

It is understood that the scope of combinations of the compounds of thisinvention with anti-HIV agents is not limited to the HIV antiviralslisted in Table A, but includes in principle any combination with anypharmaceutical composition useful for the treatment or prophylaxis ofAIDS. The HIV antiviral agents and other agents will typically beemployed in these combinations in their conventional dosage ranges andregimens as reported in the art, including, for example, the dosagesdescribed in the Physicians' Desk Reference, Thomson PDR, Thomson PDR,57^(th) edition (2003), the 58^(th) edition (2004), the 59^(th) edition(2005), and the like. The dosage ranges for a compound of the inventionin these combinations are the same as those set forth above.

The compounds of this invention are also useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention ofHIV infection can be determined by the attending clinician, taking intoconsideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the subject; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Fused Tricyclic HeterocycleDerivative(s) and the other agent(s) can be administered simultaneously(i.e., in the same composition or in separate compositions one rightafter the other) or sequentially. This particularly useful when thecomponents of the combination are given on different dosing schedules,e.g., one component is administered once daily and another component isadministered every six hours, or when the pharmaceutical compositionsare different, e.g., one is a tablet and one is a capsule. A kitcomprising the separate dosage forms is therefore advantageous.

Compositions and Administration

When administered to a subject, the Fused Tricyclic HeterocycleDerivatives can be administered as a component of a composition thatcomprises a pharmaceutically acceptable carrier or vehicle. The presentinvention provides pharmaceutical compositions comprising an effectiveamount of at least one Fused Tricyclic Heterocycle Derivative and apharmaceutically acceptable carrier. In the pharmaceutical compositionsand methods of the present invention, the active ingredients willtypically be administered in admixture with suitable carrier materialssuitably selected with respect to the intended form of administration,i.e., oral tablets, capsules (either solid-filled, semi-solid filled orliquid filled), powders for constitution, oral gels, elixirs,dispersible granules, syrups, suspensions, and the like, and consistentwith conventional pharmaceutical practices. For example, for oraladministration in the form of tablets or capsules, the active drugcomponent may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier, such as lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, talc,mannitol, ethyl alcohol (liquid forms) and the like. Solid formpreparations include powders, tablets, dispersible granules, capsules,cachets and suppositories. Powders and tablets may be comprised of fromabout 0.5 to about 95 percent inventive composition. Tablets, powders,cachets and capsules can be used as solid dosage forms suitable for oraladministration.

Moreover, when desired or needed, suitable binders, lubricants,disintegrating agents and coloring agents may also be incorporated inthe mixture. Suitable binders include starch, gelatin, natural sugars,corn sweeteners, natural and synthetic gums such as acacia, sodiumalginate, carboxymethylcellulose, polyethylene glycol and waxes. Amongthe lubricants there may be mentioned for use in these dosage forms,boric acid, sodium benzoate, sodium acetate, sodium chloride, and thelike. Disintegrants include starch, methylcellulose, guar gum, and thelike. Sweetening and flavoring agents and preservatives may also beincluded where appropriate.

Liquid form preparations include solutions, suspensions and emulsionsand may include water or water-propylene glycol solutions for parenteralinjection.

Liquid form preparations may also include solutions for intranasaladministration.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize therapeutic effects, i.e., antiviral activity and the like.Suitable dosage forms for sustained release include layered tabletscontaining layers of varying disintegration rates or controlled releasepolymeric matrices impregnated with the active components and shaped intablet form or capsules containing such impregnated or encapsulatedporous polymeric matrices.

In one embodiment, the one or more Fused Tricyclic HeterocycleDerivatives are administered orally.

In another embodiment, the one or more Fused Tricyclic HeterocycleDerivatives are administered intravenously.

In one embodiment, a pharmaceutical preparation comprising at least oneFused Tricyclic Heterocycle Derivative is in unit dosage form. In suchform, the preparation is subdivided into unit doses containing effectiveamounts of the active components.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentcompositions can contain, in one embodiment, from about 0.1% to about99% of the Fused Tricyclic Heterocycle Derivative(s) by weight orvolume. In various embodiments, the present compositions can contain, inone embodiment, from about 1% to about 70% or from about 5% to about 60%of the Fused Tricyclic Heterocycle Derivative(s) by weight or volume.

The compounds of Formula I can be administered orally in a dosage rangeof 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in asingle dose or in divided doses. One dosage range is 0.01 to 500 mg/kgbody weight per day orally in a single dose or in divided doses. Anotherdosage range is 0.1 to 100 mg/kg body weight per day orally in single ordivided doses. For oral administration, the compositions can be providedin the form of tablets or capsules containing 1.0 to 500 milligrams ofthe active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100,150, 200, 250, 300, 400, and 500 milligrams of the active ingredient forthe symptomatic adjustment of the dosage to the subject to be treated.The specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the host undergoing therapy.

For convenience, the total daily dosage may be divided and administeredin portions during the day if desired. In one embodiment, the dailydosage is administered in one portion. In another embodiment, the totaldaily dosage is administered in two divided doses over a 24 hour period.In another embodiment, the total daily dosage is administered in threedivided doses over a 24 hour period. In still another embodiment, thetotal daily dosage is administered in four divided doses over a 24 hourperiod.

The amount and frequency of administration of the Fused TricyclicHeterocycle Derivatives will be regulated according to the judgment ofthe attending clinician considering such factors as age, condition andsize of the subject as well as severity of the symptoms being treated.The compositions of the invention can further comprise one or moreadditional therapeutic agents, selected from those listed above herein.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) at least one Fused Tricyclic HeterocycleDerivative or a pharmaceutically acceptable salt thereof; (ii) one ormore additional therapeutic agents that are not a Fused TricyclicHeterocycle Derivative; and (iii) a pharmaceutically acceptable carrier,wherein the amounts in the composition are together effective to treatHIV infection.

Kits

In one aspect, the present invention provides a kit comprising atherapeutically effective amount of at least one Fused TricyclicHeterocycle Derivative, or a pharmaceutically acceptable salt or prodrugof said compound and a pharmaceutically acceptable carrier, vehicle ordiluent.

In another aspect the present invention provides a kit comprising anamount of at least one Fused Tricyclic Heterocycle Derivative, or apharmaceutically acceptable salt or prodrug of said compound and anamount of at least one additional therapeutic agent listed above,wherein the amounts of the two or more active ingredients result in adesired therapeutic effect. In one embodiment, the one or more FusedTricyclic Heterocycle Derivatives and the one or more additionaltherapeutic agents are provided in the same container. In oneembodiment, the one or more Fused Tricyclic Heterocycle Derivatives andthe one or more additional therapeutic agents are provided in separatecontainers.

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures ofwhich are incorporated herein by reference.

The invention claimed is:
 1. A compound having the formula:

and pharmaceutically acceptable salts thereof, wherein: A is C₁-C₄alkylene, C₂-C₄ alkenylene, arylene, C₃-C₇ cycloalkyl, 5 or 6-memberedmonocyclic heteroaryl, 4 to 7-membered heterocycloalkyl, —O—, —NH—C(O)—,—C(O)NH— or —C(O)—; X is O, —N(C₁-C₆ alkyl)- or —C(R¹⁰)(R¹¹), such thatwhen X═O or —N(C₁-C₆ alkyl)-, then R⁴, R⁵, R⁶ and R⁷ are each other than—OR⁹, —N(R⁹)₂ or halo; each occurrence of m is independently 0 or 1; nis 0 or 1, such that when n is 0, then R⁴ and R⁵ are not present; R¹ isC₁-C₆ alkyl, which is optionally substituted with up to 3 groups, eachindependently selected from C₃-C₇ cycloalkyl, 5 or 6-membered monocyclicheteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C₆-C₁₀ aryl,halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹and —SR⁹, wherein said C₃-C₇ cycloalkyl group, said 5 or 6-memberedmonocyclic heteroaryl group, said 4 to 6-membered monocyclicheterocycloalkyl group and said C₆-C₁₀ aryl group can each be optionallyand independently substituted with one or more groups, eachindependently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5 or6-membered monocyclic heteroaryl, 4 to 6-membered monocyclicheterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂,—C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; R², R⁵, R⁶, R⁷, R¹⁰ and R¹¹are each independently selected from H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂ and—NHC(O)R⁹, wherein said C₁-C₆ alkyl group can be optionally substitutedwith one or more groups, each independently selected from halo, —OH,—O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SH or—S(C₁-C₆ alkyl); R³ is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, —C(O)R⁹, —C(O)N(R⁹)₂ and —NHC(O)R⁹, wherein said C₁-C₆ alkylgroup can be optionally substituted with one or more groups, eachindependently selected from halo, —OH, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —SH or —S(C₁-C₆ alkyl); R⁴ is H, or R⁴ and R⁵and the common carbon atom to which they are attached, join to form anendocyclic —C(O)— group; R⁸ is selected from C₁-C₆ alkyl, —(C₁-C₃alkylene)_(m)-(C₃-C₇ cycloalkyl), —(C₁-C₃ alkylene)_(m)-(5 or 6-memberedmonocyclic heteroaryl), —(C₁-C₃ alkylene)_(m)-(4 to 6-memberedmonocyclic heterocycloalkyl) and —(C₁-C₃ alkylene)_(m)-(C₆-C₁₀ aryl),wherein said C₃-C₇ cycloalkyl group, said 5 or 6-membered monocyclicheteroaryl group, said 4 to 6-membered monocyclic heterocycloalkyl groupand said C₆-C₁₀ aryl group can each be optionally and independentlysubstituted with up to 5 groups, each independently selected from C₁-C₆alkyl, C₃-C₇ cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to6-membered monocyclic heterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆haloalkyl, —OR⁹, —N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; andeach occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.
 2. The compound of claim 1having the formula:

and pharmaceutically acceptable salts thereof, wherein: A is 5 or6-membered monocyclic heteroaryl or —NH—C(O)—; X is O, —N(C₁-C₆ alkyl)-or —C(R¹⁰)(R¹¹), such that when X═O or —N(C₁-C₆ alkyl)-, then R⁴, R⁵, R⁶and R⁷ are each other than —OR⁹, —N(R⁹)₂ or halo; n is 0 or 1, such thatwhen n is 0, then R⁴ and R⁵ are not present; R¹ is C₁-C₆ alkyl, which isoptionally substituted with a group selected from phenyl, C₃-C₇cycloalkyl, 5 or 6-membered monocyclic heteroaryl and —OR⁹, wherein saidphenyl group and said 5 or 6-membered monocyclic heteroaryl group caneach be optionally and independently substituted with up to two groups,each independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, 5 or6-membered monocyclic heteroaryl, 4 to 6-membered monocyclicheterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆ haloalkyl, —OR⁹, —N(R⁹)₂,—C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; R⁴ is H, or R⁴ and R⁵ and thecommon carbon atom to which they are attached, join to form anendocyclic —C(O)— group; R⁵, R¹⁰ and R¹¹ are each independently selectedfrom H, C₁-C₆ alkyl and —OR⁹; R⁷ is selected from H, C₁-C₆ alkyl, —OR⁹and —OH; R⁸ is selected from C₁-C₆ alkyl or benzyl, wherein the phenylmoiety of said benzyl group can be optionally and independentlysubstituted with up to 3 groups, each independently selected from C₁-C₆alkyl, C₃-C₇ cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to6-membered monocyclic heterocycloalkyl, C₆-C₁₀ aryl, halo, C₁-C₆haloalkyl, —OR⁹, —N(R⁹)₂, —C(O)R⁹, —C(O)N(R⁹)₂, —NHC(O)R⁹ and —SR⁹; andeach occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.
 3. The compound of claim 1having the formula (Ib):

and pharmaceutically acceptable salts and prodrugs thereof, wherein: Ais pyrazolyl, thiadiazolyl, triazolyl, thiazolyl, oxazolyl, oxadiazaolylor —NHC(O)—; X is O, —N(C₁-C₆ alkyl)- or —C(R¹⁰)(R¹¹), such that whenX═O or —N(C₁-C₆ alkyl)-, then R⁴, R⁵, R⁶ and R⁷ are each other than—OR⁹, —N(R⁹)₂ or halo; n is 0 or 1, such that when n is 0, then R⁴ andR⁵ are not present; R¹ is C₁-C₆ alkyl, which is optionally substitutedwith a group selected from phenyl, C₃-C₇ cycloalkyl, 5 or 6-memberedmonocyclic heteroaryl and —O—(C₁-C₆ alkyl), wherein said phenyl groupand said 5 or 6-membered monocyclic heteroaryl group can each beoptionally and independently substituted with up to two groups, eachindependently selected from C₁-C₆ alkyl, halo and —O—(C₁-C₆ alkyl); R⁴is H, or R⁴ and R⁵ and the common carbon atom to which they areattached, join to form an endocyclic —C(O)— group; R⁵, R¹⁰ and R¹¹ areeach independently selected from H, C₁-C₆ alkyl and —O—(C₁-C₆ alkyl); R⁷is selected from H, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) and —OH; R⁸ isselected from C₁-C₆ alkyl or benzyl, wherein the phenyl moiety of saidbenzyl group can be optionally and independently substituted with up to3 groups, each independently selected from C₁-C₆ alkyl, —O—(C₁-C₆ alkyl)and halo; and each occurrence of R⁹ is independently selected from H,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl and benzyl.
 4. The compoundof claim 1, wherein A is —NHC(O)—.
 5. The compound of claim 1, wherein Xis —O—; n is 1; and R⁴, R⁵ and R⁷ are each H.
 6. The compound of claim1, wherein X is —CH₂—; n is 0; and R⁷ is H or —OH.
 7. The compound ofclaim 1, wherein R⁸ is benzyl, wherein the phenyl moiety of said benzylgroup can be optionally and independently substituted with up to 3groups, each independently selected from F, Cl, and methyl.
 8. Thecompound of claim 1, wherein R¹ is C₁-C₆ alkyl, which is optionallysubstituted with a group selected from phenyl, 5 or 6-memberedmonocyclic heteroaryl, C₃-C₇ cycloalkyl and methoxy, wherein said phenylgroup and said 5 or 6-membered monocyclic heteroaryl group can each beoptionally and independently substituted with up to two groups, eachindependently selected from methoxy, C₁-C₆ alkyl and fluoro.
 9. Thecompound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 11. A method for the inhibition ofHIV integrase in a subject in need thereof which comprises administeringto the subject an effective amount of the compound according to claim 1,or a pharmaceutically acceptable salt or prodrug thereof.
 12. A methodfor the treatment of infection by HIV or for the treatment, or delay inthe onset or progression of AIDS in a subject in need thereof, whichcomprises administering to the subject an effective amount of thecompound according to claim 1, or a pharmaceutically acceptable salt orprodrug thereof.
 13. The pharmaceutical composition of claim 10, furthercomprising one or more additional therapeutic agents selected fromraltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir,atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine andlopinavir.
 14. The method of claim 12, further comprising administeringto the subject one or more additional therapeutic agents selected fromraltegravir, dolutegravir, abacavir, lamivudine, ritonavir andlopinavir, wherein the amounts administered of the compound of claim 1,and the one or more additional therapeutic agents, are togethereffective to treat infection by HIV or to treat or delay the onset orprogression of AIDS.